Alpha-substittuted pyridazino quinoline compounds

ABSTRACT

The invention relates to alpha-substituted pyridazino-quinoline compounds of the formula I:  
                 
 
     wherein Ring A is chosen from an ortho fused aromatic or heteroaromatic five- or six-membered ring; R 1  is selected from a variety of substituents including halogen, (1-4C)alkyl and nitro; R 2  is selected from a group of the formula R2′, R2″ or R2″′ wherein R2′ is —CHR 3 (CH 2 ) n C(O)NR 5 R 6 ; R2″ is —CHR 3 (CH 2 ) n R 4  and R2″′ is —CHR 3 (CH 2 ) n L wherein n is 0-6; R 5  is aryl or substituted aryl; R 6  is (1-6C)alkyl or hydrogen; R 3  is (1-6C)alkyl, (0-6C) alkylCF 3 , or (0-6C)alkylCOOR′; R 4  is (1-6C)alkyl, (2-6C)alkyl containing a double or triple bond, or (0-6C)alkylaryl; L is a variety of substituents including phenyl, heteroaryl and CO 2 R′; R′ is hydrogen or (1-4C)alkyl; Z is selected from oxo, —OH, H, H —, H, (1-6C)alkyl or (1-6C)alkylaryl; and R 7  is hydrogen or —(CO)R 8  wherein R 8  is a variety of substituents including hydrogen and (1-12C) alkyl.

[0001] This invention relates to pyridazinedione compounds useful in thetreatment of neurological disorders generally in mammals such as man.More specifically, the compounds are useful in the treatment of strokesand/or other neuro-degenerative disorders such as hypoglycemia, cerebralpalsy, transient cerebral ischemic attack, perinatal asphyxia, epilepsy,psychosis, Huntington's chorea, amyotrophic lateral sclerosis,Alzheimer's disease, Parkinson's disease, Olivo-pontocerebellar atrophy,viral-induced neurodegeneration such as in acquired immunodeficiencysyndrome and its associated dementia, anoxia such as from drowning,spinal cord and brain trauma, and chronic pain, for the prevention ofdrug and alcohol withdrawal symptoms, and for the inhibition oftolerance and dependence to opiate analgesics. The inventionparticularly relates to novel pyridazinedione compounds useful inreducing neurological degeneration such as can be induced by a strokeand the associated functional impairment which can result. Treatmentusing a compound of the invention can be remedial or therapeutic as byadministering a compound following an ischemic event to mitigate theeffects of that event. Treatment can also be prophylactic or prospectiveby administering a compound in anticipation that an ischemic event mayoccur, for example in a patient who is prone to stroke.

[0002] It is known that ischemic events can trigger a dramatic increasein extracellular concentrations of the excitatory amino acids glutamateand aspartate which can, in turn, cause prolonged neuronal excitationleading to a massive influx of calcium from extracellular tointracellular sites in brain neural cells. A calcium overload canthereby be created which leads to a cascade of events leading to cellcatabolism and eventually resulting in cell death. TheN-methyl-D-aspartate (NMDA) receptor complex is believed to play asignificant role in the cascade of events leading to cell necrosisfollowing an ischemic event.

[0003] The compounds provided by this invention may be useful in avariety of neurodegenerative disorders because they function asexcitatory amino acid antagonists. They may do so indirectly, viaallosteric modulation of the glutamate binding site, specifically byacting as antagonists of the strychnine-insensitive glycine receptor onthe NMDA receptor complex. They may also do so directly, by binding tothe glutamate site itself on the NMDA receptor complex.

[0004] A compound of formula I:

[0005] is claimed as a glycine receptor antagonist useful in thetreatment and prevention of neurological disorders and apharmaceutically acceptable salt thereof wherein,

[0006] Ring A is chosen from an ortho fused aromatic or hetero-aromaticfive- or six-membered ring selected from phenyl, pyridyl, furyl,pyrrolyl or thienyl either unsubstituted or multi-substituted at a ringcarbon atom with R¹ wherein R¹ is independently selected from the groupconsisting of halo, (1-4C)alkyl, NO₂, CN, (C1-3)perfluoroalkyl, OH,OCF₃, (2-4C)-alkenyl, (2-4C)alkynyl, O(1-4C)alkyl, NR′R″, SO₂NR′R″,SO_(m)R′, a heterocyclic group, NR′COR″, COR″, NR′CO₂R″, CO₂R′, orCONR′R″;

[0007] R² is selected from a cycloalkyl moiety of 3-7 carbon atoms;

[0008] or R² is selected from a group of the formula R2′, R2″ or R2″′

[0009] wherein R2′ is —CHR³(CH₂)_(n)C(O)NR⁵R⁶; R2 ″ is —CHR³(CH₂)_(n)R⁴and R2″′ is —CHR³(CH₂)_(n)L wherein, for a group of formula R2″′, L is Mor W;

[0010] M is

[0011] phenyl or benz derivatives thereof and is either unsubstituted orsubstituted with 1, 2, 3 or 4 groups chosen from —O-(1-4C)alkyl,—O-(2-4C)alkenyl, —O—(2-4C)alkynyl, —O(C0-C6alkyl)phenyl, —OH, -halo,—NO₂, —CN, —CF₃, -(1-4C)alkylCF₃, —NH(CO)R′, -(1-4C)alkyl, —NR′R″,—CO₂R′, —CONR′R″, —SO_(m)R′, —SO₂NR′R″, (C1-C6)alkyloxy(C1-C6)alkyloxy-,hydroxy(C1-C6)alkyloxy-, oxy(1-6C)alkyloxy which may form a cyclic ringattached to the phenyl ring in an ortho manner,aryloxy(1-4C)alkyloxy(1-4C)alkyl,(C1-C6)alkyloxy(C1-C6)alkyloxy(C1-C6)alkyloxy-,hydroxy(C1-C6)alkyloxy(C1-C6)alkyloxy-, —O(C1-C6alkyl)NR′R″,—NR′(C1-C6alkyl)NR′R″, -(C1-C6alkyl)NR′R″, —O-(1-4C)perfluroalkyl,-(1-4Cperfluroalkyl, —NR′(C1-C6alkyloxy), —NR′(C1-C6alkylhydroxy),-(C1-4alkyl)oxy(C1-4alkyl), —O(C1-4alkyl)COOR′, -(CH)_(n)NR′R″COOR′wherein n is 1-4, -(C1-4alkyl)NR′R″, -(C1-4alkyl)OR′,—NR′(CH₂)_(n)COOR′, —S(O)_(m)(C1-4alkyl)oxy(C1-4alkyl),—S(O)_(m)(C1-4alkyl)oxy(C1-4alkyl)oxy(C1-4alkyl),—NR′(C1-4alkyl)oxy(C1-4alkyl),—NR′(C1-4alkyl)oxy(C1-4alkyl)oxy(C1-4alkyl);

[0012] heterocycle wherein heterocycle is selected from a five- and/orsix- and/or seven-membered heterocyclic ring containing 1, 2,or 3heteroatoms chosen from O, N, or S, or aryl or heteroaryl benzderivatives thereof, wherein the N on the heterocycle is optionallysubstituted with R′ and a carbon or nitrogen atom on the heterocycle maybe substituted with R or R′ or a carbon atom may be disubstituted toform a C5-C7 spiral group or a carbon atom or sulfur atom may besubstituted with O to form a carbonyl group or sulfonyl group (S(O)_(m))with the proviso that a heterocyclic nitrogen may not be attached to anitrogen on the tricyclic ring system of formula I;

[0013] heteroaryl wherein heteroaryl is selected from unsubstituted orsubstituted aromatic species and benz derivatives thereof includingpyridyl, thienyl, furanyl, or those groups containing two heteroatomsselected from N, O or S such as pyrazole, imidazole, isoxazole, oxazole,thiazole or isothiazole (and oxidized versions thereof selected fromS(O)_(m) wherein m is 0-2), pyridazine, pyrimidine, pyrazine or thosegroups containing three heteroatoms chosen from N, O or S such astriazole or oxadiazole or triazine, or those groups containing fourheteroatoms such as tetrazole, wherein the N on the heteroaryl group isoptionally substituted with R and the substituted aromatic substituentsinclude typical aromatic substituents selected from hydroxy, alkoxy,halo or cyano and the heteroaryl group is attached to —(CH₂)_(n) via acarbon atom or a heteroatom on the heteroaryl group;

[0014] W is selected from OH, OR′, OCOR′, S(O)_(m)R′, S(O)_(m)NR′R″,halo, CF₃, NR′R″ or W is COR′, NR′COR″, OCONR′, NR′CO₂R″,(C3-6)cycloalkyl, NRCONR′R″, CO₂R′, or CONRR′;

[0015] n is chosen from 0-6;

[0016] Z is selected from oxo, —OH, H, H—, H,(1-6C)alkyl or(1-6C)alkylaryl wherein aryl may be substituted with a substituent orsubstituents selected from halogen, C1-6alkyl or other typical aromaticsubstituents;

[0017] R³ is selected from (1-6C)alkyl, (0-6C)alkylCF₃,(0-6C)alkyl-COOH;

[0018] R⁷ is selected from hydrogen or —(CO)R⁸ wherein R⁸ is selectedfrom (1) hydrogen, (2) (1-12C)alkyl which may contain a double or triplebond, and which may bear a group selected from (a) CN, OR^(e), andCO₂R^(e), wherein R^(e) is selected from hydrogen, (1-4C)alkyl, andphenyl and phenyl(1-4C)alkyl, the phenyl rings of which can besubstituted with from 0-3 substituents selected from halo, amino,hydroxy, cyano, nitro, (1-4C)alkyl, and (1-4C)alkoxy; (b) NR^(f) ₂ andCONR^(f) ₂ wherein each R^(f) is independently selected (1) from R^(h),COR^(h), and COOR^(h) when the said group is NR^(f) ₂ and (2) from thevalues of R^(h) when the said group is CONR^(f) ₂, wherein R^(h) canhave any of the values stated above for R^(e), or wherein, for either ofthe said groups, the two R^(f) values, together with the nitrogen towhich they are attached, form a saturated 4- to 7-membered ring, (3)NR^(g) ₂ wherein each R^(g) can independently have any of the valuesstated above for R^(e), or wherein the two R^(g) groups together withthe nitrogen to which are are attached form a saturated 4- to 7-memberedring, (4) pyridyl, pyridyl(1-12C)alkyl, (5) phenyl, andphenyl(1-4C)alkyl wherein the phenyl rings can be substituted with from0-3 substituents selected from halo, amino, hydroxy, cyano, nitro,(1-4C)alkyl, and (1-4C)alkoxy;

[0019] R is selected from H or (1-4C)alkyl;

[0020] R′ and R″ are independently selected from H, (1-4C)alkyl whereinalkyl includes alkenyl(C2-C4) and alkynyl(C2-C4); (3-6C)cycloalkyl,Phenyl(0-4C)alkyl-, heterocycle(0-4C)alkyl- or heteroaryl(0-4C)alkyl-wherein phenyl or heterocycle or heteroaryl is as defined above and anyof the above is optionally substituted at one or more carbon atoms withhalo, H, (1-4C)alkyl, (3-6C)cycloalkyl, phenyl, NO₂, CN, CF₃, OH,O—(1-4C)alkyl, NR′R″S(O)_(m)R′ or SO₂NR′R″ wherein NR′R″ may optionallyform an N-alkyl(C1-3)oxyalkyl(C2-3) ring with N; and

[0021] For a group of formula R2′, R⁵ is selected from aryl wherein thearyl group may be unsubstituted or mono- or multisubstitued with atypical aromatic substituent selected from halogen, (1-4C)alkyl, NO₂,CN, (C1-3)perfluoroalkyl, OH, OCF₃, (2-4C)alkenyl, (2-4C)alkynyl,O(1-4C)alkyl, NR′R″, SO₂NR′R″, SO_(m)R′, NR′COR″, COR″, NR′CO₂R″, CO₂R′,or CONR′R″; and R⁶ is chosen from (1-6C)alkyl or hydrogen;

[0022] For a group of formula R2″, R⁴ is selected from (1-6C)alkyl or(0-6C)alkylaryl wherein the aryl moiety may be unsubstituted orsubstituted or multisubstituted with a typical aromatic substituentselected from halogen, (1-4C)alkyl, NO₂, CN, (C1-3)perfluoroalkyl, OH,OCF₃, (2-4C)alkenyl, (2-4C)alkynyl, O(1-4C)alkyl, NR′R″, SO₂NR′R″,SO_(m)R′; or NR′COR″, COR″, NR′CO₂R″, CO₂R′, or CONR′R″;

[0023] . . . means a C—C, C—N or C—O double bond is optionally presentwith the proviso that the proper carbon or nitrogen valency may not beexceeded; a wavy line means a designated group is optionally present;

[0024] m is chosen from 0-2.

[0025] The present invention also relates to a compound of formula I:

[0026] or pharmaceutically acceptable salts thereof wherein:

[0027] Ring A is chosen from an ortho fused aromatic or hetero-aromaticfive- or six-membered ring selected from phenyl, pyridyl, furyl,pyrrolyl or thienyl either unsubstituted or multi-substituted at a ringcarbon atom with R¹ wherein R¹ is independently selected from the groupconsisting of halo, (1-4C)alkyl, NO₂, CN, (C1-3)perfluoroalkyl, OH,OCF₃, (2-4C)-alkenyl, (2-4C)alkynyl, O(1-4C)alkyl, NR′R″, SO₂NR′R″, orSO_(m)R′, a heterocyclic group, NR′COR″, COR″, NR′CO₂R″, CO₂R′, CONR′R″;

[0028] R² is selected from —CHR³(CH₂)_(n)L wherein L is M or W;

[0029] M is

[0030] phenyl or benz derivatives thereof and is either unsubstituted orsubstituted with 1, 2, 3 or 4 groups chosen from —O-(1-4C)-alkyl,—O—(2-4C)alkenyl, —O-(2-4C)alkynyl, —O(C0-6alkyl)phenyl, —OH, -halo,—NO₂, —CN, —CF₃, -(1-4C)alkylCF₃, —NH(CO)R′, -(1-4C)alkyl, —NR′R″,—CO₂R′, —CONR′R″, —SO_(m)R′, —SO₂NR′R″, (C1-C6)alkyloxy(C1-C6)alkyloxy-,hydroxy(C1-C6)alkyloxy-, oxy(1-6C)alkyloxy which may form a cyclic ringattached to the phenyl ring in an ortho manner,aryloxy(1-4C)alkyloxy(1-4C)alkyl, (C1-C6)alkyloxy(C1-C6)alkyloxy(C1-C6)alkyloxy-, hydroxy(C1-C6)alkyloxy(C1-C6)alkyloxy-,—O(C1-C6alkyl)NR′R″, —NR′(C1-C6alkyl)NR′R″, —(C1-C6alkyl)NR′R″,—O-(1-4C)perfluroalkyl, -(1-4Cperfluroalkyl, —NR′(C1-C6alkyloxy),—NR′(C1-C6alkylhydroxy), -(C1-4alkyl)oxy(C1-4alkyl), —O(C1-4alkyl)COOR′,—(CH)_(n)NR′R″COOR′ wherein n is 1-4, —(C1-4alkyl)NR′R″,-(C1-4alkyl)OR′, —NR′(CH₂)_(n)COOR′, —S(O)_(m)(C1-4alkyl)oxy(C1-4alkyl),—S(O)_(m)(C1-4alkyl)oxy(C1-4alkyl)oxy(C1-4alkyl),—NR′(C1-4alkyl)oxy(C1-4alkyl),—NR′(C1-4alkyl)oxy(C1-4alkyl)oxy(C1-4alkyl);

[0031] heterocycle wherein heterocycle is selected from a five- and/orsix- and/or seven-membered heterocyclic ring containing 1, 2,or 3heteroatoms chosen from O, N, or S, or aryl or heteroaryl benzderivatives thereof, wherein the N on the heterocycle is optionallysubstituted with R′ and a carbon or nitrogen atom on the heterocycle maybe substituted with R or R′ or a carbon atom may be disubstituted toform a C5-C7 spiral group or a carbon atom or sulfur atom may besubstituted with O to form a carbonyl group or sulfonyl group (S(O)_(m))with the proviso that a heterocyclic nitrogen may not be attached to anitrogen or the tricyclic ring system of formula I;

[0032] heteroaryl wherein heteroaryl is selected from unsubstituted orsubstituted aromatic species and benz derivatives thereof includingpyridyl, thienyl, furanyl, or those groups containing two heteroatomsselected from N, O or S such as pyrazole, imidazole, isoxazole, oxazole,thiazole or isothiazole (and oxidized versions thereof selected fromS(O)_(m) wherein m is 0-2), pyridazine, pyrimidine, pyrazine or thosegroups containing three heteroatoms chosen from N, O or S such astriazole or oxadiazole or triazine, or those groups containing fourheteroatoms such as tetrazole, wherein the N on the heteroaryl group isoptionally substituted with R and the substituted aromatic substituentsinclude typical aromatic substituents selected from hydroxy, alkoxy,halo or cyano and the heteroaryl group is attached to —(CH₂)_(n) via acarbon atom or a heteroatom on the heteroaryl group;

[0033] W is selected from OH, OR′, OCOR′, S(O)_(m)R′, S(O)_(m)NR′R″,halo, CF₃, NR′R″; or W is COR′, NR′COR″, OCONR′, NR′CO₂R″,(C3-6)cycloalkyl, NRCONR′R″, CO₂R′, or CONRR′ and

[0034] n is chosen from 0-6;

[0035] R³ is selected from (1-6C)alkyl, (0-6C)alkylCF₃ or(0-6C)alkylCOOH;

[0036] R⁷ is selected from H or —C(O)R⁸ wherein R⁸ is selected from(1-12C)alkyl which may contain a double or triple bond;

[0037] R is selected from H or (1-4C)alkyl;

[0038] R′ and R″ are independently selected from H, (1-4C)alkyl whereinalkyl includes alkenyl(C2-C4) and alkynyl(C2-C4); (3-6C)cycloalkyl,Phenyl(0-4C)alkyl-, heterocycle(0-4C)alkyl- or heteroaryl(0-4C)alkyl-wherein phenyl or heterocycle or heteroaryl is as defined above and anyof the above is optionally substituted at one or more carbon atoms withhalo, H, (1-4C)alkyl, (3-6C)cycloalkyl, phenyl, NO₂, CN, CF₃, OH,O—(1-4C)alkyl, NR′R″S(O)_(m)R′ or SO₂NR′R″ wherein NR′R″ may optionallyform an N-alkyl(C1 -3)oxyalkyl(C2-3) ring with N;

[0039] m is chosen from 0-2.

[0040] The present invention further relates to a compound of formula

[0041] and pharmaceutically acceptable salts thereof wherein:

[0042] Ring A is chosen from an ortho fused aromatic or hetero-aromaticfive- or six-membered ring selected from phenyl, pyridyl, pyrrolyl orthienyl either unsubstituted or substituted at one or more ring carbonatoms with R¹ wherein R¹ is independently selected from the groupconsisting of hydrogen, halo, (1-4C)alkyl, NO₂, CN,(C1-3)perfluoroalkyl, OH, OCF₃, (2-4C)alkenyl, (2-4C)alkynyl,O(1-4C)alkyl, NR′R″, SO₂NR′R″, or SO_(m)R′;

[0043] R² is —CHR³(CH₂)_(n)L wherein

[0044] L is chosen from:

[0045] —OH, —O(C1-C4alkyl), —O(C1-C4alkyl)aryl, (C1-C4alkyl)COOR′,OCOR′, S(O)_(m)R′, NR′R″ with the proviso that NR′R″, NR′COR″, OCONR′,NR′CO₂R″, NRCONR′R″, CO₂R′, or CONRR′;

[0046] phenyl or benz derivatives thereof and is either unsubstituted orsubstituted with 1, 2, 3 or 4 groups chosen from —O—(1-4C)alkyl,—O—(2-4C)alkenyl, —O—(2-4C)alkynyl, —O(C0-C6alkyl)phenyl, —OH, -halo,—NO₂, —CN, —CF₃, -(1-4C)alkylCF₃, —NH(CO)R′, —(1-4C)alkyl, —NR′R″,—CO₂R′, —CONR′R″, —SO_(m)R′, —SO₂NR′R″, (C1-C6)alkyloxy(C1-C6)alkyloxy-,hydroxy(C1-C6)alkyloxy-, oxy(1-6C)alkyloxy which may form a cyclic ringattached to the phenyl ring in an ortho manner,aryloxy(1-4C)alkyloxy(1-4C)alkyl,(C1-C6)alkyloxy(C1-C6)alkyloxy(C1-C6)alkyloxy-,hydroxy(C1-C6)alkyloxy(C1-C6)alkyloxy-, —O(C1-C6alkyl)NR′R″,—NR′(C1-C6alkyl)NR′R″, -(C1-C6alkyl)NR′R″, —O—(1-4C)perfluroalkyl,-(1-4Cperfluroalkyl, —NR′(C1-C6alkyloxy), —NR′(C1-C6alkylhydroxy),-(C1-4alkyl)oxy(C1-4alkyl), —O(C1-4alkyl)COOR′, —(CH)_(n)NR′R″COOR′wherein n is 1-4, -(C1-4alkyl)NR′R″, -(C1-4alkyl)OR′,—NR′(CH₂)_(n)COOR′, —S(O)_(m)(C1-4alkyl)oxy(C1-4alkyl),—S(O)_(m)(C1-4alkyl)oxy(C1-4alkyl)oxy(C1-4alkyl),—NR′(C1-4alkyl)oxy(C1-4alkyl),—NR′(C1-4alkyl)oxy(C1-4alkyl)oxy(C1-4alkyl);

[0047] heterocycle wherein heterocycle is selected from a five- and/orsix- and/or seven-membered heterocyclic ring containing 1, 2,or 3heteroatoms chosen from O, N, or S wherein the N on the heterocycle isoptionally substituted with R′ and a carbon or nitrogen atom on theheterocycle may be substituted with R or R′ or a carbon atom may bedisubstituted to form a C5-C7 spiral group or a carbon atom or sulfuratom may be substituted with O to form a carbonyl group or sulfonylgroup (S(O)_(m)); wherein the heterocyclic groups may be selected from,for example, 2-pyrolidinone, piperazine, oxazolidone,2,5-oxazolidinedione, 2,4-imidazollidinedione, 2,4-thiazolidinedione orsuccinimide; aryl or benz or heteroarylbenz derivatives thereof(3,4-pyridinedicarboximide, -1-pthalimido, isatoic anhydride,orthobenzoic-sulfimide) either unsubstituted or mono, bi ortri-substituted with alkyl or aromatic substituents including -halo,-C1-C6alkyl, —OH, C1-C6alkoxy, phenyl, OCF₃, CF₃, NO₂, CN, NH₂,SO_(m)R′, NH(C1-4alkyl), or N(C1-C4alkyl)₂;

[0048] heteroaryl wherein heteroaryl is selected from unsubstituted orsubstituted aromatic species and benz derivatives thereof includingpyridyl, thienyl, furanyl, or those groups containing two heteroatomsselected from N, O or S such as pyrazole, imidazole, isoxazole, oxazole,thiazole, isothiazole, or those groups containing three heteroatomschosen from N, O or S such as triazole or oxadiazole or those groupscontaining 4 heteroatoms such as tetrazole wherein the N on theheteroaryl group is optionally substituted with R and the substitutedaromatic substituents include typical aromatic substituents selectedfrom hydroxy, alkoxy, halo or cyano and the heteroaryl group is attachedto —(CH₂)_(n) via a carbon atom or a heteroatom on the heteroaryl group;n is 0-3; R, R³, R⁷, R⁸, R′, R″ and m are as previously defined.

[0049] The present invention further relates to a compound of formula I:

[0050] and pharmaceutically acceptable salts thereof wherein:

[0051] Ring A is chosen from an ortho fused aromatic or heteroaromaticfive- or six-membered ring selected from phenyl, pyridyl, pyrrolyl orthienyl either unsubstituted or substituted at one or more ring carbonatoms with R¹ wherein R¹ is independently selected from the groupconsisting of hydrogen, halo, (1-4C)alkyl, NO₂, CN,(C1-3)perfluoroalkyl, OH, OCF₃, (2-4C)alkenyl, (2-4C)alkynyl,O(1-4C)alkyl, NR′R″, SO₂NR′R″, or SO_(m)R′;

[0052] R² is —CHR³(CH₂)_(n)L wherein

[0053] L is chosen from:

[0054] phenyl or benz derivatives thereof and is either unsubstituted orsubstituted with 1, 2, 3 or 4 groups chosen from —O—(1-4C)alkyl,—O—(2-4C)alkenyl, —O—(2-4C)alkynyl, —O(C0-C6alkyl)phenyl, —OH, -halo,—NO₂, —CN, —CF₃, -(1-4C)alkylCF₃, —NH(CO)R′, -(1-4C)alkyl, —NR′R″,—CO₂R′, —CONR′R″, —SO_(m)R′, —SO₂NR′R″, (C1-C6)alkyloxy(C1-C6)alkyloxy-,hydroxy(C1-C6)alkyloxy-, oxy(1-6C)alkyloxy which may form a cyclic ringattached to the phenyl ring in an ortho manner,aryloxy(1-4C)alkyloxy(1-4C)alkyl,(C1-C6)alkyloxy(C1-C6)alkyloxy(C1-C6)alkyloxy-,hydroxy(C1-C6)alkyloxy(C1-C6)alkyloxy-, —O(C1-C6alkyl)NR′R″,—NR′(C1-C6alkyl)NR′R″, -(C1-C6alkyl)NR′R″, —O—(1-4C)perfluroalkyl,-(1-4C)perfluroalkyl, —NR′(C1-C6alkyloxy), —NR′(C1-C6alkylhydroxy),-(C1-4alkyl)oxy(C1-4alkyl), —O(C1-4alkyl)COOR′, —(CH)_(n)NR′R″COOR′wherein n is 1-4, -(C1-4alkyl)NR′R″, -(C1-4alkyl)OR′,—NR′(CH₂)_(n)COOR′, —S(O)_(m)(C1-4alkyl)oxy(C1-4alkyl)—S(O)_(m)(C1-4alkyl)oxy(C1-4alkyl)oxy(C1-4alkyl),—NR′(C1-4alkyl)oxy(C1-4alkyl),—NR′(C1-4alkyl)oxy(C1-4alkyl)oxy(C1-4alkyl);

[0055] heteroaryl wherein heteroaryl is selected from unsubstituted orsubstituted aromatic species and benz derivatives thereof includingpyridyl, thienyl, furanyl, or those groups containing two heteroatomsselected from N, O or S such as pyrazole, imidazole, isoxazole, oxazole,thiazole, isothiazole, or those groups containing three heteroatomschosen from N, O or S such as triazole or oxadiazole or those groupscontaining 4 heteroatoms such as tetrazole wherein the N on theheteroaryl group is optionally substituted with R and the substitutedaromatic substituents include typical aromatic substituents selectedfrom hydroxy, alkoxy, halo or cyano and the heteroaryl group is attachedto —(CH₂)_(n) via a carbon atom or a heteroatom on the heteroaryl group;

[0056] n is 0; R, R³, R⁷, R⁸, R′, R″ and m are as defined previously.

[0057] In addition, the invention relates to a compound of formula I:

[0058] or a pharmaceutically acceptable salt thereof wherein:

[0059] Ring A is chosen from an ortho fused aromatic or hetero-aromaticfive- or six-membered ring selected from phenyl, pyridyl, pyrrolyl orthienyl either unsubstituted or substituted at one or more ring carbonatoms with R¹ wherein R¹ is independently selected from the groupconsisting of hydrogen, halo, (1-4C)alkyl, NO₂, CN,(C1-3)perfluoroalkyl, OH, OCF₃, (2-4C)alkenyl, (2-4C)alkynyl,O(1-4C)alkyl, NR′R″, SO₂NR′R″, or SO_(m)R′;

[0060] R² is —CHR³(CH₂)_(n)L wherein

[0061] L is chosen from:

[0062] —OH, —O(C1-C4alkyl),CF₃—O(C1-C4alkyl)aryl, (C1-C4alkyl)COOR′,OCOR′, S(O)_(m)R′, NR′R″, NR′COR″, OCONR′, NR′CO₂R″, NRCONR′R″, CO₂R′,or CONRR′;

[0063] phenyl or benz derivatives thereof and is either unsubstituted orsubstituted with 1, 2, 3 or 4 groups chosen from —O-(1-4C)alkyl,—O-(2-4C)alkenyl, —O-(2-4C)alkynyl, —O(C0-C6alkyl)phenyl, —OH, -halo,—NO₂, —CN, —CF₃, -(1-4C)alkylCF₃, —NH(CO)R′, -(1-4C)alkyl, —NR′R″,—CO₂R′, —CONR′R″, —SO_(m)R′, —SO₂NR′R″, (C1-C6)alkyloxy(C1-C6)alkyloxy-,hydroxy(C1-C6)alkyloxy-, oxy(1-6C)alkyloxy which may form a cyclic ringattached to the phenyl ring in an ortho manner,aryloxy(1-4C)alkyloxy(1-4C)alkyl,(C1-C6)alkyloxy(C1-C6)alkyloxy(C1-C6)alkyloxy-,hydroxy(C1-C6)alkyloxy(C1-C6)alkyloxy-, —O(C1-C6alkyl)NR′R″,—NR′(C1-C6alkyl)NR′R″, -(C1-C6alkyl)NR′R″, —O-(1-4C)perfluroalkyl,-(1-4Cperfluroalkyl, —NR′(C1-C6alkyloxy), —NR′(C1-C6alkylhydroxy),-(C1-4alkyl)oxy(C1-4alkyl), —O(C1-4alkyl)COOR′, —(CH)_(n)NR′R″COOR′wherein n is 1-4, -(C1-4alkyl)NR′R″, -(C1-4alkyl)OR′, —NR′(CH₂)NCOOR′,—S(O)_(m)(C1-4alkyl)oxy(C1-4alkyl),—S(O)_(m)(C1-4alkyl)oxy(C1-4alkyl)oxy(C1-4alkyl),—NR′(C1-4alkyl)oxy(C1-4alkyl),—NR′(C1-4alkyl)oxy(C1-4alkyl)oxy(C1-4alkyl);

[0064] heterocycle wherein heterocycle is selected from a five- and/orsix- and/or seven-membered heterocyclic ring containing 1, 2,or 3heteroatoms chosen from O, N, or S wherein the N on the heterocycle isoptionally substituted with R′ and a carbon or nitrogen atom on theheterocycle may be substituted with R or R′ or a carbon atom may bedisubstituted to form a C5-C7 spiral group or a carbon atom or sulfuratom may be substituted with O to form a carbonyl group or sulfonylgroup (S(O)_(m)); wherein the heterocyclic groups may be selected from,for example, 2-pyrolidinone, piperazine, oxazolidone,2,5-oxazolidinedione, 2,4-imidazollidinedione, 2,4-thiazolidinedione orsuccinimide; aryl or benz or heteroarylbenz derivatives thereof(3,4-pyridinedicarboximide, -1-pthalimido, isatoic anhydride,orthobenzoicsulfimide) either unsubstituted or mono, bi ortri-substituted with alkyl or aromatic substituents including -halo,-C1-C6alkyl, —OH, C1-C6alkoxy, phenyl, OCF₃, CF₃, NO₂, CN, NH₂,SO_(m)R′, NH(C1-4alkyl), or N(C1-C4alkyl)₂;

[0065] heteroaryl wherein heteroaryl is selected from unsubstituted orsubstituted aromatic species and benz derivatives thereof includingpyridyl, thienyl, furanyl, or those groups containing two heteroatomsselected from N, O or S such as pyrazole, imidazole, isoxazole, oxazole,thiazole, isothiazole, or those groups containing three heteroatomschosen from N, O or S such as triazole or oxadiazole or those groupscontaining 4 heteroatoms such as tetrazole wherein the N on theheteroaryl group is optionally substituted with R and the substitutedaromatic substituents include typical aromatic substituents selectedfrom hydroxy, alkoxy, halo or cyano and the heteroaryl group is attachedto —(CH₂)_(n) via a carbon atom or a heteroatom on the heteroaryl group;

[0066] n is 1; R, R³, R⁷, R⁸, R′, R′ and m are as previously defined.

[0067] The invention also relates to a compound of formula I:

[0068] or pharmaceutically acceptable salts thereof wherein:

[0069] Ring A is chosen from an ortho fused aromatic or hetero-aromaticfive- or six-membered ring selected from phenyl, pyridyl, pyrrolyl orthienyl either unsubstituted or substituted at one or more ring carbonatoms with R¹ wherein R¹ is independently selected from the groupconsisting of hydrogen, halo, (1-4C)alkyl, NO₂, CN,(C1-3)perfluoroalkyl, OH, OCF₃, (2-4C)alkenyl, (2-4C)alkynyl,O(1-4C)alkyl, NR′R″, SO₂NR′R″, or SO_(m)R′;

[0070] R² is —CHR³(CH₂)_(n)L wherein

[0071] L is chosen from:

[0072] —OH, —O(C1-C4alkyl), CF₃—O(C1-C4alkyl)aryl, (C1-C4alkyl)CO₂R′,OCOR′, S(O)_(m)R′, NR′R″, NR′COR″, OCONR′, NR′CO₂R″, NRCONR′R″, CO₂R′,or CONRR′;

[0073] phenyl or benz derivatives thereof and is either unsubstituted orsubstituted with 1, 2, 3 or 4 groups chosen from —O-(1-4C)alkyl,—O-(2-4C)alkenyl, —O-(2-4C)alkynyl, —O(C0-C6alkyl)phenyl, —OH, -halo,—NO₂, —CN, —CF₃, -(1-4C)alkylCF₃, —NH(CO)R′, -(1-4C)alkyl, —NR′R″,—CO₂R′, —CONR′R″, —SO_(m)R′, —SO₂NR′R″, (C1-C6)alkyloxy(C1-C6)alkyloxy-,hydroxy(C1-C6)alkyloxy-, oxy(1-6C)alkyloxy which may form a cyclic ringattached to the phenyl ring in an ortho manner,aryloxy(1-4C)alkyloxy(1-4C)alkyl,(C1-C6)alkyloxy(C1-C6)alkyloxy(C1-C6)alkyloxy-,hydroxy(C1-C6)alkyloxy(C1-C6)alkyloxy-, —O(C1-C6alkyl)NR′R″,—NR′(C1-C6alkyl)NR′R″, -(C1-C6alkyl)NR′R″, —O-(1-4C)perfluroalkyl,-(1-4C)perfluroalkyl, —NR′(C1-C6alkyloxy), —NR′(C1-C6alkylhydroxy),-(C1-4alkyl)oxy(C1-4alkyl), —O(C1-4alkyl)COOR′, —(CH)_(n)NR′R′COOR′wherein n is 1-4, -(C1-4alkyl)NR′R″, -(C1-4alkyl)OR′,—NR′(CH₂)_(n)COOR′, —S(O)_(m)(C1-4alkyl)oxy(C1-4alkyl),—S(O)_(m)(C1-4alkyl)oxy(C1-4alkyl)oxy(C1-4alkyl), —NR′(C1-4alkyl)oxy(C1-4alkyl), —NR′(C1-4alkyl)oxy(C1-4alkyl)oxy(C1-4alkyl);

[0074] heterocycle wherein heterocycle is selected from a five- and/orsix- and/or seven-membered heterocyclic ring containing 1, 2,or 3heteroatoms chosen from O, N, or S wherein the N on the heterocycle isoptionally substituted with R′ and a carbon or nitrogen atom on theheterocycle may be substituted with R or R′ or a carbon atom may bedisubstituted to form a C5-C7 spiral group or a carbon atom or sulfuratom may be substituted with O to form a carbonyl group or sulfonylgroup (S(O)_(m)); wherein the heterocyclic groups may be selected from,for example, 2-pyrolidinone, piperazine, oxazolidone,2,5-oxazolidinedione, 2,4-imidazollidinedione, 2,4-thiazolidinedione orsuccinimide; aryl or benz or heteroarylbenz derivatives thereof(3,4-pyridinedicarboximide, -1-pthalimido, isatoic anhydride,orthobenzoic-sulfimide) either unsubstituted or mono, bi ortri-substituted with alkyl or aromatic substituents including -halo,-C1-C6alkyl, —OH, C1-C6alkoxy, phenyl, OCF₃, CF₃, NO₂, CN, NH₂,SO_(m)R′, NH(C1-4alkyl), or N(C1-C4alkyl)₂;

[0075] heteroaryl wherein heteroaryl is selected from unsubstituted orsubstituted aromatic species and benz derivatives thereof includingpyridyl, thienyl, furanyl, or those groups containing two heteroatomsselected from N, O or S such as pyrazole, imidazole, isoxazole, oxazole,thiazole, isothiazole, or those groups containing three heteroatomschosen from N, O or S such as triazole or oxadiazole or those groupscontaining 4 heteroatoms such as tetrazole wherein the N on theheteroaryl group is optionally substituted with R and the substitutedaromatic substituents include typical aromatic substituents selectedfrom hydroxy, alkoxy, halo or cyano and the heteroaryl group is attachedto —(CH₂)_(n) via a carbon atom or a heteroatom on the heteroaryl group;

[0076] n is 2; R, R³, R⁷, R⁸, R′, R″ and m are as previously defined.

[0077] The N-2 substituted derivatives recited above are readilyprepared by reacting the appropriate BOC-protected —CHR³(CH₂)_(n)L (asR²) hydrazine as shown generally below with the appropriate2-pyrrolidinocarbamide-3-carboxylic acid precurser. The general reactionbetween the R²-substituted hydrazine and the2-pyrrolidinocarbamide-3-carboxylic acid (reacted with DCC) can be usedto selectively produce the N-2 R² substituted PQD derivative wherein R²may be chosen from any of the groups recited above in the definition ofR².

[0078] The present invention preferably relates to a compound of formulaI or Ia-Id:

[0079] or a pharmaceutically acceptable salt thereof and tautomersthereof wherein:

[0080] Ring A is chosen from an ortho fused aromatic or heteroaromaticfive- or six-membered ring selected from phenyl, pyridyl, furyl,pyrrolyl or thienyl either unsubstituted or multi-substituted at a ringcarbon atom with R¹ wherein R¹ is independently selected from the groupconsisting of halo, (1-4C)alkyl, NO₂, CN, (C1-3)perfluoroalkyl, OH,OCF₃, (2-4C)alkenyl, (2-4C)alkynyl, O(1-4C)alkyl, NR′R″, SO₂NR′R″,SO_(m)R′; NR′COR″, COR″, NR′CO₂R″, CO₂R′, CONR′R″;

[0081] R² is selected from a group of the formula R²′ or R²″

[0082] wherein,

[0083] n is 0-2;

[0084] R³ is selected from (1-6C)alkyl, (0-6C)alkylCF₃, (0-6C)alkylCOOH;

[0085] For a group of formula R2′, R⁵ is selected from aryl wherein thearyl group may be unsubstituted or mono- or multi-substituted with atypical aromatic substituent selected from alogen, (1-4C)alkyl, NO₂, CN,(C1-3)perfluoroalkyl, OH, OCF₃, (2-4C)alkenyl, (2-4C)alkynyl,O(1-4C)alkyl, NR′R″, SO₂NR′R″, or SO_(m)R′;

[0086] NR′COR″, COR″, NR′CO₂R″, CO₂R′, CONR′R″; and R⁶ is chosen from(1-6C)alkyl or hydrogen;

[0087] For a group of formula R2″, R⁴ is selected from (1-6C)alkyl or(0-6C)alkylaryl wherein the aryl moiety may be unsubstituted orsubstituted or multisubstituted with a typcial aromatic substituentselected from halogen, (1-4C)alkyl, NO₂, CN, (C1-3)perfluoroalkyl, OH,OCF₃, (2-4C)alkenyl, (2-4C)alkynyl, O(1-4C)alkyl, NR′R″, SO₂NR′R″, orSO_(m)R′; NR′COR″, COR″, NR′CO₂R″, CO₂R′, CONR′R″;

[0088] R′ and R″ are independently selected from H, (1-4C)alkyl whereinalkyl includes alkenyl(C2-C4) and alkynyl(C2-C4); or (3-6C)cycloalkyl;or Phenyl(0-4C)alkyl- wherein the phenyl ring may be unsubstituted orsubstituted with a typical aromatic substituent as recited above;

[0089] R⁷ is selected from H or (1-6C)C(O)—;

[0090] or

[0091] R² is selected from a cycloalkyl moiety of 3-7 carbon atoms;

[0092] . . . means a C—C, C—N or C-0 double bond is optionally presentwith the proviso that the proper carbon or nitrogen valency may not beexceeded; a wavy line means a designated group is optionally present;

[0093] Z is selected from H, —OH, oxo or H,H;

[0094] m is chosen from 0-2.

[0095] The present invention also relates to a compound of formulaIa-Id:

[0096] or pharmaceutically acceptable salts thereof:

[0097] wherein:

[0098] R¹ is an aromatic subsituent on the phenyl A ring of the A-B-Ctricylic ring system wherein the phenyl ring may be unsubstituted ormono-, bi-, tri- or tetrasubstituted with R¹ wherein R¹ is selected fromhalogen, (1-4C)alkyl, NO₂, CN, (C1-3)perfluoroalkyl, OH, OCF₃,(2-4C)alkenyl, (2-4C)alkynyl, O(1-4C)alkyl, NR′R″, SO₂NR′R″, orSO_(m)R′; NR′COR″, COR″, NR′CO₂R″, CO₂R′, CONRR″;

[0099] R² is selected from a group of the formula R²′ or R²″,

[0100] wherein,

[0101] n is 0-2;

[0102] R³ is selected from (1-6C)alkyl, (0-6C)alkylCF₃, (0-6C)alkylCOOH;

[0103] For a group of formula R2′, R⁵ is selected from aryl wherein thearyl group may be unsubstituted or mono- or multisubstitued with atypical aromatic substituent selected from halogen, (1-4C)alkyl, NO₂,CN, (C1-3)perfluoroalkyl, OH, OCF₃, (2-4C)alkenyl, (2-4C)alkynyl,O(1-4C)alkyl, NR′R″, SO₂NR′R″, or SO_(m)R′; NR′COR″, COR″, NR′CO₂R″,CO₂R′, CONR′R″; and R⁶ is chosen from (1-6C)alkyl or hydrogen;

[0104] For a group of formula R2″, R⁴ is selected from (1-6C)alkyl or(0-6C)alkylaryl wherein the aryl moiety may be unsubstituted orsubstituted or multisubstituted with a typcial aromatic substituentselected from halogen, (1-4C)alkyl, NO₂, CN, (C1-3)perfluoroalkyl, OH,OCF₃, (2-4C)alkenyl, (2-4C)alkynyl, O(1-4C)alkyl, NR′R″, SO₂NR′R″, orSO_(m)R′; NR′COR″, COR″, NR′CO₂R″, CO₂R′, CONR′R″;

[0105] R′ and R″ are independently selected from H, (1-4C)alkyl whereinalkyl includes alkenyl(C2-C4) and alkynyl(C2-C4); or (3-6C)cycloalkyl;or Phenyl(0-4C)alkyl- wherein the phenyl ring may be unsubstituted orsubstituted with a typical aromatic substituent as recited above;

[0106] R⁷ is selected from H or (1-3C)alkylC(O)—;

[0107] or

[0108] R² is selected from a cycloalkyl moiety of 3-7 carbon atoms;

[0109] m is chosen from 0-2.

[0110] The present invention further relates to compounds of the FormulaI:

[0111] or a pharmaceutically acceptable salt thereof; and/or a tautomerthereof and/or a solvate thereof; and/or a hydrate thereof; and/or astereoisomer thereof; wherein:

[0112] Ring A is chosen from an ortho fused aromatic or heteroaromaticfive- or six-membered ring selected from phenyl, pyridyl, furyl,pyrrolyl or thienyl either unsubstituted or multi-substituted at a ringcarbon atom with R¹ wherein R¹ is independently selected from the groupconsisting of halo, (1-4C)alkyl, NO₂, CN, (C1-3)perfluoroalkyl, OH,OCF₃, (2-4C)alkenyl, (2-4C)alkynyl, O(1-4C)alkyl, NR′R″, SO₂NR′R″,SO_(m)R′, a heterocyclic group, NR′COR″, COR″, NR′CO₂R″, CO₂R′, orCONR′R″;

[0113] R² is selected from a cycloalkyl moiety of 3-7 carbon atoms; orR² is selected from a group of the formula R2′, R2″ or R2″ wherein R2′is —CHR³(CH₂)_(n)C(O)NR⁵R⁶; R2″ is —CHR³(CH₂)_(n)R⁴ and R2″′ is—CHR³(CH₂)_(n)L wherein, for a group of formula R2″′, L is M or W;

[0114] M is

[0115] phenyl or benz derivatives thereof and is either unsubstituted orsubstituted with 1, 2, 3 or 4 groups chosen from —0-(1-4C)alkyl,—O—(2-4C)alkenyl, —O-(2-4C)alkynyl, —O(C0-C6alkyl)phenyl, —OH, -halo,—NO₂, —CN, —CF₃, -(1-4C)alkylCF₃, —NH(CO)R′, -(1-4C)alkyl, —NR′R″,—CO₂R′, —CONR′R″, —SO_(m)R′, —SO₂NR′R″, (C1-C6)alkyloxy(C1-C6)alkyloxy-,hydroxy(C1-C6)alkyloxy-, oxy(1-6C)alkyloxy which may form a cyclic ringattached to the phenyl ring in an ortho manner,aryloxy(1-4C)alkyloxy(1-4C)alkyl,(C1-C6)alkyloxy(C1-C6)alkyloxy(C1-C6)alkyloxy-,hydroxy(C1-C6)alkyloxy(C1-C6)alkyloxy-, —O(C1-C6alkyl)NR′R″,—NR′(C1-C6alkyl)NR′R″, -(C1-C6alkyl)NR′R″, —O-(1-4C)perfluroalkyl,-(1-4C)perfluroalkyl, —NR′(C1-C6alkyloxy), —NR′(C1-C6alkylhydroxy),-(C1-4alkyl)oxy(C1-4alkyl), —O(C1-4alkyl)COOR′, —(CH)_(n)NR′R″COOR′wherein n is 1-4, -(C1-4alkyl)NR′R″, —(C1-4alkyl)OR′,—NR′(CH₂)_(n)COOR′, —S(O)_(m)(C1-4alkyl)oxy(C1-4alkyl)—S(O)_(m)(C1-4alkyl)oxy(C1-4alkyl)oxy(C1-4alkyl),—NR′(C1-4alkyl)oxy(C1-4alkyl),—NR′(C1-4alkyl)oxy(C1-4alkyl)oxy(C1-4alkyl);

[0116] heterocycle wherein heterocycle is selected from a five- and/orsix- and/or seven-membered heterocyclic ring containing 1, 2, or 3heteroatoms chosen from O, N, or S, or aryl or heteroaryl benzderivatives thereof, wherein the N on the heterocycle is optionallysubstituted with R′ and a carbon or nitrogen atom on the heterocycle maybe substituted with R or R′ or a carbon atom may be disubstituted toform a C5-C7 spiral group or a carbon atom or sulfur atom may besubstituted with O to form a carbonyl group or sulfonyl group (S(O)_(m))with the proviso that a heterocyclic nitrogen may not be attached to anitrogen on the tricyclic ring system of formula I;

[0117] heteroaryl wherein heteroaryl is selected from unsubstituted orsubstituted aromatic species and benz derivatives thereof includingpyridyl, thienyl, furanyl, or those groups containing two heteroatomsselected from N, O or S such as pyrazole, imidazole, isoxazole, oxazole,thiazole or isothiazole (and oxidized versions thereof selected fromS(O)_(m) wherein m is 0-2), pyridazine, pyrimidine, pyrazine or thosegroups containing three heteroatoms chosen from N, O or S such astriazole or oxadiazole or triazine, or those groups containing fourheteroatoms such as tetrazole, wherein the N on the heteroaryl group isoptionally substituted with R and the substituted aromatic substituentsare selected from hydroxy, alkoxy, halo or cyano and the heteroarylgroup is attached to —(CH₂)_(n) via a carbon atom or a heteroatom on theheteroaryl group;

[0118] W is selected from OH, OR′, OCOR′, S(O)_(m)R′, S(O)_(m)NR′R″,halo, CF₃, NR′R″ or W is COR′, NR′COR″, OCONR′, NR′CO₂R″,(C3-6)cycloalkyl, NRCONR′R″, CO₂R′, or CONRR′;

[0119] n is chosen from 0-6;

[0120] Z is selected from oxo, —OH, H, H—, H,(1-6C)alkyl or(1-6C)alkylaryl wherein aryl may be substituted with a substituent orsubstituents selected from halogen or C1-6alkyl;

[0121] R³ is selected from (1-6C)alkyl, (0-6C)alkylCF₃,(0-6C)alkylCOOR′;

[0122] R⁷ is selected from hydrogen or —(CO)R⁸ wherein R⁸ is selectedfrom (1) hydrogen, (2) (1-12C)alkyl which may contain a double or triplebond, and which may bear a group selected from (a) CN, OR^(e), andCO₂R^(e), wherein R^(e) is selected from hydrogen, (1-4C)alkyl, andphenyl and phenyl(l-4C)alkyl, the phenyl rings of which can besubstituted with from 0-3 substituents selected from halo, amino,hydroxy, cyano, nitro, (1-4C)alkyl, and (1-4C)alkoxy; (b) NR^(f) ₂ andCONR^(f) ₂ wherein each R^(f) is independently selected (1) from R^(h),COR^(h), and COOR^(h) when the said group is NR^(f) ₂ and (2) from thevalues of R^(h) when the said group is CONR^(f) ₂, wherein R^(h) canhave any of the values stated above for R^(e), or wherein, for either ofthe said groups, the two R^(f) values, together with the nitrogen towhich they are attached, form a saturated 4- to 7-membered ring, (3)NR^(g) ₂ wherein each R^(g) can independently have any of the valuesstated above for R^(e), or wherein the two R^(g) groups together withthe nitrogen to which are attached form a saturated 4- to 7-memberedring, (4) pyridyl, pyridyl(1-12C)alkyl, (5) phenyl, andphenyl(1-4C)alkyl wherein the phenyl rings can be substituted with from0-3 substituents selected from halo, amino, hydroxy, cyano, nitro,(1-4C)alkyl, and (1-4C)alkoxy;

[0123] R is selected from H or (1-4C)alkyl;

[0124] R′ and R″ are independently selected from H, (1-4C)alkyl whereinalkyl includes alkenyl(C2-C4) and alkynyl(C2-C4); (3-6C)cycloalkyl,Phenyl(0-4C)alkyl-, heterocycle(0-4C)alkyl- or heteroaryl(0-4C)alkyl-wherein phenyl or heterocycle or heteroaryl is as defined above and anyof the above is optionally substituted at one or more carbon atoms withhalo, H, (1-4C)alkyl, (3-6C)cycloalkyl, phenyl, NO₂, CN, CF₃, OH,O-(1-4C)alkyl, NR′R″S(O)_(m)R′ or SO₂NR′R″ wherein NR′R″ may optionallyform an N-alkyl(C1-3)oxyalkyl(C2-3) ring with N; for a group of formulaR2′, R⁵ is selected from aryl wherein the aryl group may beunsubstituted or mono- or multisubstituted with a substituent selectedfrom halogen, (1-4C)alkyl, NO₂, CN, (C1-3)perfluoroalkyl, OH, OCF₃,(2-4C)alkenyl, (2-4C)alkynyl, O(1-4C)alkyl, NR′R″, SO₂NR′R″, SO_(m)R′,NR′COR″, COR″, NR′CO₂R″, CO₂R′, or CONR′R″; and R⁶ is chosen from(1-6C)alkyl or hydrogen;

[0125] for a group of formula R2″, R⁴ is selected from (1-6C)alkyl,(2-6C)alkyl containing a double or triple bond, or (0-6C)alkylarylwherein the aryl moiety may be unsubstituted or substituted ormultisubstituted with a substituent selected from halogen, (1-4C)alkyl,NO₂, CN, (C1-3)perfluoroalkyl, OH, OCF₃, (2-4C)alkenyl, (2-4C)alkynyl,O(1-4C)alkyl, NR′R″, SO₂NR′R″, SO_(m)R′, NR′COR″, COR″, NR′CO₂R″, CO₂R′,or CONR′R″; and

[0126] m is chosen from 0-2.

[0127] Compounds within the ambit of Formula I above are those of theFormula Ia:

[0128] wherein R¹, R² and R⁷ are as described directly above.

[0129] Preferred compounds of the Formula Ia above are those wherein:

[0130] the Ring A phenyl ring is mono, di or trisubstituted with R¹wherein R¹ is selected from halo, (1-4C)alkyl or nitro;

[0131] R² is selected from a cycloalkyl moiety of 5-7 carbon atoms, orR² is selected from a group of the Formulas R2′, R2″ or R2″′ wherein nis chosen from 0-2; R⁵ is phenyl wherein the phenyl group isunsubstituted or mono- or multisubstituted with a substituent selectedfrom halogen, (1-4C)alkyl, NO₂, CN, (C1-3)perfluoroalkyl, OH, OCF₃,(2-4C)alkenyl, (2-4C)alkynyl, or O(1-4C)alkyl; R⁶ is chosen from(1-3C)alkyl or hydrogen; R⁴ is selected from (1-3C)alkyl or(0-3C)alkylphenyl wherein the phenyl moiety is unsubstituted orsubstituted with a substituent selected from halogen, (1-4C)alkyl, NO₂,CN, (C1-3)perfluoroalkyl, OH, OCF₃, (2-4C)alkenyl, (2-4C)alkynyl, orO(1-4C)alkyl; L is phenyl, or CO₂R wherein R′ is hydrogen or(1-4C)alkyl;

[0132] R⁷ is selected from hydrogen or (1-3C)alkyl C(O)- and R³ is asdefined directly above.

[0133] Particularly preferred compounds of the Formula Ia above arethose wherein:

[0134] the ring A phenyl ring is mono-substituted with R¹ wherein R¹ ishalo;

[0135] R² is cyclohexyl, or R² is selected from a group of the FormulasR2′, R2″ or R2″′ wherein n is 0-2;

[0136] R⁵ is phenyl wherein the phenyl group is unsubstituted; R⁴ is(1-3C)alkyl or (0-3C)alkylphenyl wherein the phenyl moiety isunsubstituted; L is phenyl or CO₂R wherein R′ is hydrogen or(1-4C)alkyl;

[0137] R⁷ is hydrogen and R³ and R⁶ are as defined directly above.

[0138] Especially particularly preferred compounds of the Formula Iaabove are those wherein:

[0139] the Ring A phenyl ring is mono-substituted with R¹ wherein R¹ ischloro;

[0140] R²is cyclohexyl, or R² is selected from a group of the formulaR2′, R2″ or R2″′ wherein n is 0-2; R⁵ is phenyl; R⁶ is hydrogen ormethyl; R⁴ is methyl, isopropyl, or phenyl; L is phenyl or CO₂R′ whereinR′ is hydrogen or methyl;

[0141] R⁷ is hydrogen; and

[0142] R³is methyl, trifluoromethyl, CO₂H or CO₂CH₃.

[0143] Preferred species of the Formula Ia are those selected from thegroup consisting of:

[0144]7-chloro-4-hydroxy-2-[1-(N-phenylcarbamoyl)ethyl]-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione,

[0145] 7-chloro-4-hydroxy-2-cyclohexyl-1,2,5,10-tetrahydro-pyridazino[4,5-b]quinoline-1,10-dione,

[0146]7-chloro-4-hydroxy-2-(1-methylbenzyl)-1,2,5,10-tetra-hydropyridazinoc[4,5-b]quinoline-1,10-dione,

[0147]7-chloro-4-hydroxy-2-(-1-methylbutyl)-1,2,5,10-tetra-hydropyridazino[4,5-b]quinoline-1,10-dione,

[0148]7-chloro-4-hydroxy-2-(1-methyl-2-phenylethyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione,

[0149]7-chloro-4-hydroxy-2-(-1,3-dimethylbutyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione,

[0150]7-chloro-4-hydroxy-2-[(R)-l-(methyloxy-carbonyl)ethyl]-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione,

[0151]7-chloro-4-hydroxy-2-[1-(methyloxycarbonyl)benzyl]-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione,

[0152]7-chloro-4-hydroxy-2-[1-(N-phenyl-N-methylcarbamoyl)ethyl]-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione,

[0153]7-chloro-4-hydroxy-2-[1-methyl-2-(N-phenylcarbamoyl)-ethyl]-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione,

[0154]7-chloro-4-hydroxy-2-[1-methyl-2-(N-phenyl-N-methyl-carbamoyl)ethyl]1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione,

[0155]7-chloro-4-hydroxy-2-(l-trifluoromethylbenzyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione,

[0156]7-chloro-4-hydroxy-2-(1-carboxybenzyl)-1,2,5,10-tetra-hydropyridazino[4,5-b]quinoline-1,10-dione, and

[0157]7-chloro-4-hydroxy-2-[(R)-1-carboxyethyl]-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione.

[0158] The present invention also relates to a pharmaceuticalcomposition comprising a compound of formula I or Ia-Id with thevariables recited above and a pharmaceutically acceptable excipient ordiluent.

[0159] The invention further relates to a method for the treatment ofneurological disorders comprising administering to a patient in need ofsuch treatment an effective amount of a compound of the Formula I, orIa-Id.

[0160] The present invention also relates to a method of treating orpreventing ischemic damage in a patient in need of such treatmentcomprising administering a pharmaceutically effective amount of acompound of formula I or Ia-Id with the variables as recited above tosaid patient.

[0161] The invention further relates to a method of treating orpreventing neurological damage associated with excitatory amino acids ina patient in need of such treatment comprising administering apharmaceutically effective amount of a compound of formula I or Ia-Id tosaid patient.

[0162] The invention also relates to a method of treating stroke orepileptic convulsions or diseases or disorders associated with excessivecalcium influx in the brain caused by excitatory amino acids comprisingadministering to a patient in need of treatment thereof apharmaceutically effective amount of a compound of formula I or Ia-Id.

[0163] The invention further relates to a process for producing acompound of formula I or Ia-Id, comprising:

[0164] treating any of the compounds of formula Ia produced in step (a)recited in the following pages with a reducing agent under suitableconditions to form a compound of formula Ib and further treating acompound of formula Ib with a reducing agent under the appropriateconditions to form a compound of formula Ic.

[0165] The invention further relates to a process for producing acompound of formula I or Ia-Id according to certain steps recited aboveor as shown in the examples wherein the compounds are selected from:

[0166] (a)7-chloro-4-hydroxy-2-[1-(phenylcarbamoyl)ethyl]-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione;

[0167] (b)7-chloro-4-hydroxy-2-cyclohexyl-1,2,5,10-tetra-hydropyridazino[4,5-b]quinoline-1,10-dione;

[0168] (c) 7-chloro-4-hydroxy-2-(alpha-methylbenzyl)-1,2,5,10-tetrahydropyridazino[ 4,5-b]quinoline-1,10-dione;

[0169] (d)7-chloro-4-hydroxy-2-(1-methylbutyl)-1,2,5,10-tetra-hydropyridazino[4,5-b]quinoline-1,10-dione;

[0170] (e) 7-chloro-4-hydroxy-2-(alpha-methylphenethyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione; and

[0171] (f)7-chloro-4-hydroxy-2-(1,3-dimethylbutyl)1,2,5,10-tetra-hydropyridazino[4,5-b]quinoline-1,10-dione.

[0172] The invention further relates to a process for producing acompound of the Formula I which comprises:

[0173] (a) reacting a compound of the Formula IV:

[0174] with a hydrazine of the formula:

[0175] to produce a compound of the Formula II

[0176] and (b) reacting said compound of the Formula II with an acid toafford the compounds of the Formula I.

[0177] The invention also relates to the use of a compound of formula Ior Ia-Id in medicine and to diseases or disorders associated withexcitatory amino acids.

[0178] The invention further relates to the use of a compound of theFormula I or Ia-Id for the preparation of a medicament for the treatmentof neurological disorders.

[0179] The invention also relates to the use of a compound of formula Ior Ia-Id for the treatment or prevention of stroke or epilepticconvulsions or disorders or conditions associated with excessive influxof calcium ions in the brain. None of the compounds recited herein haveproduced any untoward side effects.

[0180] The present invention also relates to compounds which are usefulas key intermediates in the production of glycine receptor antagonists.Key intermediates include 3-carboxylic acid quinoline 2-pyrrolidineamidecompounds which are utilized to react with BOC-protected substitutedhydrazines to form, after coupling with dicyclohexyldiimide ordiisopropyldiimide or 1-cyclohexyl-3-(2-morpholinyl-ethyl)-carbodiimide, in a polar solvent such as THF, methanol, diethylether,dioxane, CH₂Cl₂, CH₃CN or DMF and an acid (e.g. CH₃SO₃H) to producea-pyrrolidiiocarbamide 3 carboxylic acid-N-1 R²-substituted hydrazide,which after deprotection or removal of the BOC or other bulkN-protection group, leads selectively to the N-2 substituted PQD. (SeeScheme 1, formula II and III) wherein R² is defined as recited herein.The pyrrolidine may be substituted with an equivalent amine whichproduces an amide with limited steric hindrance and which acts as anappropriate leaving group.

[0181] EPO publication number 0 516 297 A1 describes certainpyridazinediones. In addition, the compounds (1)thieno[2′,3′:5,6]pyrido[2,3-d]pyridazine-5,8,9(4H,6H,7H)-trione and (2)thieno[3′,2′:5,6]pyrido[2,3-d]pyridazine-4,5,8(6H,7H,9H)-trione areknown, for example from J. Heterocyclic Chem., 28, 205, (1991).

[0182] Other pyridazinedione compounds are known from, for example,Beilstein's Handbuch der Organischen Chemie; Godard et. al., Bull. Soc.Chim. Fr., 1588, (1972); and Reid et. al., Chem. Ber., 85, 204, (1952).The compounds of the present invention, on the other hand, relate tonovel 2-substituted pyridazinediones or tautomers thereof as shown abovein formula I or Ia-Id with the variables as recited above.

[0183] Particular subgroups within the above broadly defined group ofcompounds include those compounds having the specific formulae Iwherein:

[0184] Ring A is chosen from an ortho fused aromatic or hetero-aromaticfive- or six-membered ring selected from phenyl, pyridyl, pyrrolyl orthienyl either unsubstituted or substituted at one or more ring carbonatoms with R¹ wherein R¹ is independently selected from the groupconsisting of hydrogen, halo, (1-4C)alkyl, NO₂, CN,(C1-3)perfluoroalkyl, OH, OCF₃, (2-4C)alkenyl, (2-4C)alkynyl,O(1-4C)alkyl, NR′R″, SO₂NR′R″, or SO_(m)R′;

[0185] R² is selected from a group of the formula R2′ or R2″

[0186] wherein,

[0187] n is 0-2;

[0188] R³ is selected from (1-6C)alkyl, (0-6C)alkylCF₃, (0-6C)alkylCOOH;

[0189] For a group of formula R2′, R⁵ is selected from aryl wherein thearyl group may be unsubstituted or mono- or multi-substituted with atypical aromatic substituent selected from halogen, (1-4C)alkyl, NO₂,CN, (C1-3)perfluoroalkyl, OH, OCF₃, (2-4C)alkenyl, (2-4C)alkynyl,O(1-4C)alkyl, NR′R″, SO₂NR′R″, or SO_(m)R′; NR′COR″, COR″, NR′CO₂R″,CO₂R′, CONR′R″; and R⁶ is chosen from (1-6C)alkyl or hydrogen;

[0190] For a group of formula R2″, R⁴ is selected from (1-6C)alkyl or(0-6C)alkylaryl wherein the aryl moiety may be unsubstituted orsubstituted or multisubstituted with a typical aromatic substituentselected from halogen, (1-4C)alkyl, NO₂, CN, (C1-3)perfluoroalkyl, OH,OCF₃, (2-4C)alkenyl, (2-4C)alkynyl, O(1-4C)alkyl, NR′R″, SO₂NR′R″, orSO_(m)R′; NR′COR″, COR″,NR′CO₂R″, CO₂R′, CONR′R″;

[0191] R′ and R″ are independently selected from H, (1-4C)alkyl whereinalkyl includes alkenyl(C2-C4) and alkynyl(C2-C4); or (3-6C)cycloalkyl;or Phenyl(0-4C)alkyl- wherein the phenyl ring may be unsubstituted orsubstituted with a typical aromatic substituent as recited above;

[0192] or

[0193] R² is selected from a cycloalkyl moiety of 3-7 carbon atoms;

[0194] . . . means a C—C, C—N or C-0 double bond is optionally presentwith the proviso that the proper carbon or nitrogen valency may not beexceeded; a wavy line means a designated group is optionally present;

[0195] m is chosen from 0-2; and pharmaceutically acceptable saltsthereof. The present invention also relates to pharmaceuticalcompositions of a compound of formula I as defined above and apharmaceutically acceptable excipient. In addition, the presentinvention relates to important intermediates which are useful in thesynthesis of a compound of formula I.

[0196] More particular subgroups include those compounds having thespecific formulae Ia or Ib,

[0197] wherein

[0198] the phenyl ring is mono, di or tri-substituted with R¹ wherein R¹is selected from halo, nitro or simple C1-C4alkyl including methyl,ethyl or propyl;

[0199] R² is selected from R2′ or R2″ as shown above wherein,

[0200] n is 0-2;

[0201] R³ is selected from (1-3C)alkyl, CF₃ or COOH;

[0202] For a group of formula R2′, R⁵ is selected from phenyl whereinthe phenyl group may be unsubstituted or mono- or multi-substitued witha typical aromatic substituent selected from halogen, (1-4C)alkyl, NO₂,CN, (C1-3)perfluoroalkyl, OH, OCF₃, (2-4C)alkenyl, (2-4C)alkynyl,O(1-4C)alkyl; and R⁶ is chosen from (1-3C)alkyl or hydrogen;

[0203] For a group of formula R2″, R⁴ is selected from (1-3C)alkyl or(0-3C)alkylphenyl wherein the phenyl moiety may be unsubstituted orsubstituted or multisubstituted with a typcial aromatic substituentselected from halogen, (1-4C)alkyl, NO₂, CN, (C1-3)perfluoroalkyl, OH,OCF₃, (2-4C)alkenyl, (2-4C)alkynyl, O(1-4C)alkyl;

[0204] or

[0205] R² is selected from a cycloalkyl moiety of 5-7 carbon atoms.

[0206] Preferably, the present invention relates to compounds of formulaIa:

[0207] or pharmaceutically acceptable salts thereof wherein the phenylring unsubstituted or substituted and is selected from phenyl,7-chlorophenyl, 7,9-dichlorophenyl, 7-chloro-9-methylphenyl,7-methyl,9-chlorophenyl, 7,9-dimethylphenyl, 7-chloro-8-nitrophenyl,7,9-dichloro-8-nitrophenyl, 7-chloro-9-ethylphenyl wherein the numericdesignations refer to the position on the final pyridazino quinolinering system; R² is selected from cyclohexyl, alpha-methylbenzyl,1-methylbutyl, 1-(phenylcarbamoyl)ethyl, alpha-methylphenethyl or1,3-di-methylbutyl; R⁷ is selected from H or acetyl. When R⁷ is acetyl,the compounds may act as a pro-drug and hydrolyze under physiologicalconditions to the active parent compound or may be active per se as themono-acetylated derivative. The most preferred R¹ substituent is7-chloro. The preferred group for R⁵ is phenyl; and for R⁶ is methyl orhydrogen. The preferred group for R⁴ is a C3-6 straight or branded chainhydrocarbon (depending upon the value for n) or a phenyl ring (e.g.OCalkylphenyl).

[0208] The present invention also relates to pharmaceutical compositionscontaining a preferred compound of formula Ia as shown above and apharmaceutically acceptable carrier.

[0209] It will be appreciated that the formulae described herein can bedrawn in various tautomeric and positional isomeric forms, as discussedbelow. The present invention includes such alternate forms unlessotherwise indicated, also includes salts thereof, especially thepharmaceutically acceptable addition salts.

[0210] It will be appreciated that some of the compounds disclosedherein can exist and be drawn in various true tautomeric forms (i.e.,imine to enamine conversion in the B ring).

[0211] It will further be appreciated by those skilled in the art thatcertain compounds of formula I may contain an asymmetrically substitutedcarbon atom, and accordingly may exist in, and be isolated in,optically-active and racemic forms. Some compounds may exhibitpolymorphism. It is to be understood that the present inventionencompasses any racemic, optically-active, polymorphic or stereoisomericform, or mixtures thereof, which form possesses properties useful in thetreatment of neurodegenerative disorders, it being well known in the arthow to prepare optically-active forms (for example, by resolution of theracemic form or by synthesis from optically-active starting materials)and how to determine neuroprotective properties by the standard testsdescribed hereinafter.

[0212] The invention further provides a method for the treatment ofneurological disorders, comprising administering to a mammal in need ofsuch treatment an effective amount of a compound according to theinvention as defined above, or a pharmaceutically acceptable saltthereof, or a composition as defined above. The invention alsoencompasses a method of antagonizing an NMDA receptor in mammalscomprising administering a pharmaceutically effective amount of thecompound or its salt as claimed herein or a pharmaceutical compositionas recited herein to a patient in need of treatment thereof. Thepreferred therapeutic treatment area is prevention and/or treatment ofstroke. A pharmaceutically effective amount of a compound as claimed anddisclosed in the present invention may be administered immediately afteran ischemic event to prevent cell damage and/or cell death. The presentinvention is also directed to a method of preventing and/or treatingdamage induced by the excitatory amino acids such as L-glutamate. Theinvention also relates to a method of preventing the excessive influx ofcalcium ions in central neurons. The invention relates to a method ofpreventing ischemic neuronal injury following transient global ischemiaand a method of reducing infarct volume following focal ischemic insultsby treating a patient in need of treatment thereof with apharmaceutically effective amount of a compound of formula Ia whereinthe variables for R¹ and R² are as defined herein. In addition to beinguseful in the treatment of acute stroke patients, the compounds andcompositions of the invention may be extremely beneficial in preventingneurological morbidity during cardiac resuscitation or administered ascerebral prophylatics during high-risk surgery.

[0213] In this specification the terms “alkyl” and “alkoxyl” includeboth straight and branched chain radicals, but it is to be understoodthat references to individual radicals such as “propyl” or “propoxy”embrace only the straight chain (“normal”) radical, branched chainisomers such as “isopropyl” or “isopropoxy” being referred tospecifically.

[0214] The term “halo” is inclusive of fluoro, chloro, bromo, and iodounless noted otherwise.

[0215] The term cycloalkyl moiety of 3-7 carbon atoms means cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cyclo-heptyl, preferablycyclohexyl.

[0216] Particular values of (1-3C)alkyl include methyl, ethyl, propyl,isopropyl.

[0217] Particular values of (2-4C)alkyl containing a double or triplebond include vinyl, 2-propenyl (i.e. allyl), 2-propynyl, (i.e.propargyl), 2-butenyl, and 3-butenyl.

[0218] Particular values of (1-4C)alkoxy include methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, and t-butoxy.

[0219] Particular values of (1-6C)alkyl include methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,neopentyl, hexyl, isohexyl.

[0220] Particular values of (2-6C)alkyl containing a double or triplebond include vinyl, 2-propenyl (i.e. allyl), 2-propynyl, (i.e.propargyl), but-2-enyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-pentynyl,5-hexenyl, 5-hexynyl.

[0221] Particular values of phenyl substituted with from 0-4substituents may include but are not limited to phenyl; 2-, 3-, and4-halophenyl; 2-, 3-, and 4-aminophenyl; 2-, 3-, and 4-hydroxyphenyl;2-, 3-, and 4-cyanophenyl; 2-, 3-, and 4-nitrophenyl; 2-, 3-, and4-methylphenyl; 2-, 3-, and 4-ethylphenyl; 2-, 3-, and 4-propylphenyl;2,3 or 4-isopropylphenyl; 2-, 3-, and 4-methoxyphenyl; 2-, 3-, and4-ethoxyphenyl; 2-, 3-, and 4-propoxyphenyl; and 3,5-dihalophenyl,3-halo-4-hydroxyphenyl, and 3,5-dihalo-4-hydroxyphenyl and phenylsubstituted at 1, 2 or 3 carbon atoms with methoxyethyloxy,methoxyethyloxyethyloxy, N,N-dimethylethyloxy, andN,N-dimethylethylaminyl; 3,4-dimethoxy; 3,4-dihydroxy; 3,5-dimethoxy;3,5-dihydroxy or 2,3,4-SMe or 2,3,4-SH and further includes groupsselected from 4-(SO₂CH₃)phenyl, 2-methyl-4-chlorophenyl,2,4-dihalophenyl, 4(tetrazole)phenyl, 3,5-trifluoromethyl-phenyl,2,4-dimethylphenyl, 3-halo-4-methylphenyl, 4-trifluoromethylphenyl,3,4-dimethylphenyl, 2-methyl-4-methoxyphenyl, 2-methoxy-4-halophenyl,2-methyl-4-hydroxyphenyl, 2,3-dimethylphenyl, 2,4-dimethoxyphenyl,2,5-dimethoxyphenyl, 2,5-dimethylphenyl, 4(benyloxy)phenyl,4-(ethoxy)phenyl, 2,5-dihydroxyphenyl, 4-vinyl-phenyl, 2,5-dihalophenyl,2-methyl-4-fluorophenyl, or 2,3 or 4 (CONR′R″)phenyl.

[0222] Particular values of phenyl(1-4C)alkyl substituted with from 0-4substituents may include benzyl, phenylethyl, phenylpropyl, phenylbutyl;2-, 3-, 4 and 5-halobenzyl; 2-, 3- and 4- CF₃-benzyl, 2-, 3-, and4-aminobenzyl; 2-,3-, and 4-cyanobenzyl, 2-, 3-, and 4-nitrobenzyl, 2-,3-, and 4-methylbenzyl; 2-, 3-, and 4-ethylbenzyl; 2-, 3-, and4-propylbenzyl; 2-, 3-, and 4-hydroxybenzyl; 2-, 3-, and4-methoxybenzyl; 2-, 3-, and 4-ethoxybenzyl; 2-, 3-, and4-propoxybenzyl; and 3,5-dihalobenzyl, 3-halo-4-hydroxybenzyld3,5-diCF₃benzyl and 3,5-dihalo-4-hydroxybenzyl or2,3,4,5,6-pentahalobenzyl; and phenyl(l-4C)alkyl substituted withmethoxyethyloxy, methoxyethyloxyethyloxy, N,N-dimethyl-ethyloxy, andN,N-dimethylethylaminyl; 3,4-dimethoxy; 3,4-dihydroxy; 3,5-dimethoxy;3,5-dihydroxy or 2,3,4-SMe or 2,3,4-SH.

[0223] More particular values of halo include chloro and bromo.

[0224] More particular values of (1-3C)perfluoroalkyl includetrifluoromethyl and pentafluoroethyl.

[0225] More particular values of 4- to 7-membered rings containingnitrogen include piperidino, piperazinyl and pyrrolidinyl.

[0226] More particular values of (1-3C)alkyl substituted with atrifluoromethyl group include trifluoromethylmethyl and2-trifluoromethylethyl.

[0227] More particular values of m include 0-2.

[0228] More particular values of n include 0-2.

[0229] More particular values of phenyl substituted with from 0-3substituents may include phenyl; 2- and 4-halophenyl; 2- and4-aminophenyl; 2-, 3- and 4-hydroxyphenyl; 2-, 3- and 4-methoxyphenyl;2,4-dihalophenyl; 3,5-dihalophenyl; 2,6-dihalo-4-hydroxyphenyl,2-halo-4-methylphenyl;2-methoxy-4-methylphenyl;2-methyl-4-methoxyphenyl; 3-hydroxy-4-methylphenyl; 2-hydroxy-4-methyl phenyl, 2-methyl-4-chlorophenyl,2,4-dimethylphenyl, 3,4-dimethoxyphenyl, 2-methyl-4-methoxyphenyl,3,4-dihydroxyphenyl or 2,4-dimethylphenyl; and includes those valuesspecifically exemplified in the examples.

[0230] More particular values of phenyl(C1-C4)alkyl substituted with 0-3substituents may include benzyl; phenylethyl; 2- and 4-halobenzyl; 2-and 4-cyanobenzyl; 2- and 4-nitrobenzyl; 2- and 4-methoxybenzyl;2,4-dihalobenzyl, 3,5-dihalobenzyl; and 2,6-dihalo-4-hydroxybenzyl. Thecorresponding phenethyl isomers may also be included.

[0231] Preferred compounds having formula I include:

[0232] (a)7-chloro-4-hydroxy-2-[1-(phenylcarbamoyl)ethyl]-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione;

[0233] (b)7-chloro-4-hydroxy-2-cyclohexyl-1,2,5,10-tetra-hydropyridazino[4,5-b]quinoline-1,10-dione;

[0234] (c)7-chloro-4-hydroxy-2-(alpha-methylbenzyl)-1,2,5,10-tetra-hydropyridazino[4,5-b]quinoline-1,10-dione;

[0235] (d)7-chloro-4-hydroxy-2-(1-methylbutyl)-1,2,5,10-tetra-hydropyridazino[4,5-b]quinoline-1,10-dione;

[0236] (e)7-chloro-4-hydroxy-2-(alpha-methylphenethyl)-1,2,5,10-tetra-hydropyridazino[4,5-b]quinoline-1,10-dione; and

[0237] (f)7-chloro-4-hydroxy-2-(1,3-dimethylbutyl)1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione. Of course, because of the convenient andeasy preparation of the starting N′-R² substituted BOC protectedhydrazines, the above compounds are non-limiting and include any of thecompounds within the generic scope as recited previously.

[0238] Pyridazinediones of formula I (or other formulae as recitedherein) can be made by processes which include processes known in thechemical arts for the production of structurally analogous compounds.The preparation of compounds wherein Z is H on certain startingmaterials described herein can be affected by chlorinating the hydroxygroup of the dialkyl 4-OH quinoline-2,3-dicarboxylate (startingmaterial) using phosphorous oxychloride. This chlorine is then reducedusing tetrakistriphenylphosphine Pd(O) and sodium formate to providedimethyl quinoline-2,3-dicarboxylate which is then processed through theremaining chemical steps (e.g. adding the hydrazine etc.) The processesfor the manufacture of a starting pyridazinedione of formula I asdefined above are provided to show the preparation of the preferredstarting materials utilized in the present invention and are illustratedby the following procedures in which the meanings of generic radicalsare as given above unless otherwise qualified. Such a process can beeffected, generally,

[0239] (a) to obtain a compound of formula I via a process as describedherein is achieved according to the general procedure described inScheme 1 and specifically exemplified in non-limiting examples 1-14. A2-pyrrolidinocarbamide quinoline 3 carboxylic acid, prepared fromhydrolysis of the corresponding 3-methyl ester which is prepared byreacting the corresponding 3 carbomethoxy quinoline 2 carboxylic acidwith dicyclohexylcarbodimide or other appropriate diimide couplingreagent such as diisopropyl carbodiimide and pyrollidine, is reactedwith an N-t-butoxycarbonyl-N′-2-CHR³(CH₂)_(n)L (or replace L with —R⁴ or—C(O)NR⁵SR⁶) (n=0-4) hydrazine (prepared from the reaction of either (a)t-butylcarbazate and the desired C1-C4 alkylaryl or a substituted alkylaryl or an alkoxy alkyl compound wherein the terminal alkyl carbon has asuitable leaving group selected from halo (X) or triflate in a solventsuch as DMF, CH₂Cl₂ or CH₃CN or equivalent and a base such as NEt₃ or,other groups which may readily react with t-butylcarbazate to form astarting disubstituted hydrazine t-butylO(CO)—N—N—R² include anyalkylaryl, aryloxyalkyl, alkyloxyalkyl, alkyloxyalkyloxy oralkylheteroaryl recited herein wherein the alkyl group has a suitableleaving group. For n=0-4, a suitable aryl or substituted aryl aldehydeor substituted alkylaldehyde with t-butylcarbazate in refluxing hexanesor equivalent organic solvent to form the corresponding imine which isthen reduced with a reducing agent (e.g. BH₃ THF or LiAlH₄) to obtain akey intermediate hydrazide which is cyclized in CH₃SO₃H/THF orequivalent solvent to selectively form a 2-substituted -(CR³H) (CH₂)_(n)aryl or —(CR³H)(CH₂)_(n) alkyl aryl PQD or —(CR³H)(CH₂)_(n) substitutedalkyl PQD. This process may generally be utilized to selectively form acompound of formula I. t-butylcarbazate is commercially available andthe R²-substituted t-butyl carbonate hydrazines are readily prepared. Asdescribed in the examples, there are at least three ways to prepare thestarting substituted hydrazines-methods X, Y and Z (See Scheme 2). As isreadily apparent from Scheme 2, the starting halides, aldehydes oralcohol are easily prepared or are commercially available.

[0240] A compound of formula I wherein L is a hetero-cyclic moiety suchas a 4-(C1-C6)substituted piperazine or 4-arylsubstituted piperazine ora phthalimido or another commercially available nucleophilic heterocyclemay be formed by reacting the heterocyclic nucleophilic species with a2-halo(CH₂)_(n)CR³alkyl pyridazino[4,5-b]quinolines of formula I, thelatter of which is prepared from the corresponding hydroxy species. Asthe following examples will show, compounds within the scope of thepresent invention are prepared by a variety of chemical synthetic stepsor procedures. Compounds of formula I wherein Z is (C1-6)alkyl or(C1-6)alkylaryl may be prepared from the corresponding compound offormula I with Z as oxo by alkyl or alkylaryl addition to the B-ringcarbonyl of the PQD systems. Grignard reactions using ZMgX or couplingsystems with alkyl lithium anions (e.g. ZLi or ZM) or a Wittig reactionusing Ph³P-C(RR′) may be utilized to form a precursor to a compound offormula I which is subsequently reduced or modified and reduced to forma compound of formula I wherein Z is alkyl or alkyl aryl.

[0241] In the case of alkylation or benzylation of the B-ring carbonyl,it may be necessary to perform the reaction on a pre-coupled precusorwhich is also nitrogen-protected. This would avoid unselectivealkylation at the C-ring carbonyls. However, it may also be possible toprotect the C-ring carbonyl(s) before alkylating (with ZM) the B-ringcarbonyl.

[0242] In general, Schemes 1 and 2 describe how some of the compoundswithin the scope of the present invention or intermediates are prepared.The preferred compounds are those of formula Ia. The preferred processfor producing compounds of formula Ia involves (i) preparing anintermediate PQD of formula II and III which is then cyclized to acompound of formula Ia (R⁷=H). This compound may be reduced to acompound of formula Ib or Ic under the conditions as described below(see Scheme 1). The preferred reduction conditions involve suspending acompound of formula Ia (specifically prepared as shown in examples 1-6)in an organic solvent selected from, but not limited to, THF withsubsequent addition of trifluoroacetic acid (significant molar excess).This suspension is cooled to about 0° C. and sodium borohydride is addedin molar excess (5× or less). The reduction is then allowed to proceedat 0° C. for about 15 minutes and then warmed to room temperature andstirred for about 3 hours. Upon work-up and after triturating andfiltering (2×), the title compounds are readily obtained. The preferredgroup for Z on a compound of formula I is oxygen. Z, in a compound offormula I, may also be hydrogen, OH SH or NHR or as otherwise describedherein. Key intermediates are shown in the Schemes or described in thetext.

[0243] As exemplified in a non-limiting manner in the examples, a keyprocess for selectively producing N—2—(CHR³) (CH₂)n aryl, —(CHR³) (CH₂)nheteroaryl, substituted alkyl or other species prepared from any N-2intermediates involves the initial production of a 2-pyrrolidinoamidosubstituted quinoline which is formed from the corresponding 2-carboxy3-carboalkoxy quinoline. This compound or analogous compounds (e.g. withgroups equivalent to pyrrolidinoamido) is hydrolyzed to form thecorresponding 2-pyrrolidinoamido-3-carboxy quinoline (IV) which is thencoupled with the selected R²—N—N—C(O)0-t-butyl hydrazine using aselected dimide (e.g. DCC or equivalent) to form a hydrazideintermediate— e.g. 2-pyrrolidinoamido-3-carboxylic acid-NR²-N(BOC)hydrazide which, under the cyclization conditions, forms the N-2substituted PQD without any N-3 substituted PQD formed. For example, thealpha methyl benzyl or substituted benzyl compounds described herein arereadily and conveniently prepared from the appropriate2-pyrrolidinoamido 3-carboxylic acid and theN-alphamethylbenzylN′-t-butyl carboxy hydrazine which was actuallyprepared from the corresponding alkylhalide and t-butyl carbazate.t-Butylcarbazate reacts readily to displace the halide or alcohol suchas triflate to form the desired hydrazine.

[0244] Another intermediate and glycine receptor antagonist includesN-2-alpha substituted (1-6C)alkylaryl PQDs of formula I substituted witha cyano substitutent or substituents. This moiety (CN) can be furthermanipulated to form carboxylic acids, carbonyl halides, esters, amides,or tetrazoles. As indicated previously, anion displacement (nucleophilicdisplacement) is utilized to produce various heterocyclic compounds orbenz or heteroaryl benz derivatives thereof which are glycine receptorantagonists. An N-2 halo(C1-4) alkyl PQD is reacted with the selectednucleophile (heterocyclic or heteroaryl) to form the corresponding N-2Nucleophile-(C1-4) alkyl PQD.

[0245] If not commercially available, the necessary starting materialsfor the procedures such as that described above may be made byprocedures which are selected from standard organic chemical techniques,techniques which are analogous to the synthesis of known, structurallysimilar compounds, or techniques which are analogous to the abovedescribed procedure or the procedures described in the examples.

[0246] Examples of suitable pharmaceutically acceptable salts are saltsformed with bases which form a physiologically acceptable cation, suchas alkali metal (especially lithium, sodium and potassium), alkalineearth metal (especially calcium and magnesium), aluminum and ammoniumsalts, as well as salts made with appropriate organic bases such ascholine hydroxide, triethylamine, morpholine, piperidine,ethylene-diamine, lysine, ethanolamine, diethanolamine,triethanol-amine, N-methyl-D-glucamine (meglumine), arginine, andtris(hydroxymethyl)aminomethane. Choline, meglumine, sodium andpotassium salts are preferred. Choline, sodium and potassium salts areespecially preferred.

[0247] When used to intervene therapeutically following a stroke, apyridazinedione of formula I or Ia-Id generally is administered as anappropriate pharmaceutical composition which comprises a compoundaccording to the invention as defined hereinbefore together with apharmaceutically acceptable diluent or carrier, the composition beingadapted for the particular route of administration chosen. Suchcompositions are provided as a further feature of the invention. Theymay be obtained employing conventional procedures and excipients andbinders and may be in a variety of dosage forms. For example, they maybe in the form of tablets, capsules, solutions or suspensions for oraladministration; in the form of suppositories for rectal administration;in the form of sterile solutions or suspensions for administration byintravenous or intramuscular injection or infusion; and in the form ofpowders together with pharmaceutically acceptable inert solid diluentssuch as lactose for administration by insufflation.

[0248] The dose of a compound according to the invention which isadministered will necessarily be varied according to principles wellknown in the art taking account of the route of administration, theseverity of the postischemic disorder, and the size and age of thepatient. In general, a compound of according to the invention will beadministered to a warm blooded animal (such as man) so that an effectivedose is received, generally a dose in the range of about 0.01 to about100 mg/kg body weight. For example, if the compound is administeredintravenously, it is administered in the range of about 0.01 to about 10mg/kg body weight. If it is administered orally, it is administered inthe range of about 0.5 to about 100 mg/kg body weight.

[0249] It will be apparent to those skilled in the art that a compoundaccording to the invention can be co-administered with other therapeuticor prophylactic agents and/or medicaments that are not medicallyincompatible therewith. In general, representative compounds of theinstant invention do not show any indication of significiant toxicity inlaboratory test animals.

[0250] The actions of compounds according to the invention asantagonists at the glycine receptor of the NMDA receptor complex can beshown by one or more standard tests such as the [³H]-glycine bindingassay (Test A) and by tests in vivo such as the red nucleus test (TestB) and the Rat Middle Cerebral Artery test (Test C). These tests confirmthat compounds of the invention are NMDA receptor antagonists in vitroand in vivo. Certain compounds of the invention are potent NMDA receptorantagonists.

[0251] Test A

[0252] In the [³H]-glycine binding assay, neuronal synaptic membranesare prepared from adult (about 250 g) male Sprague-Dawley rats. Freshlydissected cortices and hippocampi are homogenized in 0.32 M sucrose (110mg/mL). Synaptosomes are isolated by centrifugation (1000 xg, 10 min),the supernatant is pelleted (20,000 xg, 20 min) and resuspended indouble-distilled water. The suspension was centrifuged for 20 minutes at8,000 xg. The resulting supernatant and buffy coat are washed twice(48,000 xg, 10 mins, resuspension in double-deionized water). The finalpellet is quickly frozen (dry ice/ethanol bath) under double-deionizedwater and stored at −70° C.

[0253] On the day of the experiment, thawed synaptic membranes arehomogenized with a Brinkmann Polytron (tm, Brinkmann Instruments,Westbury, N.Y.) tissue homogenizer in 50 millimolartris(hydroxymethyl)aminomethane citrate, pH 7.1. The membranes areincubated with 0.04% Sufact-AMPS X100 (tm, Pierce, Rockford, Ill.) inbuffer for 20 minutes at 37° C. and washed six times by centrifugation(48,000 xg, 10 min) and resuspended in buffer. The final pellet ishomogenized at 200 mg wet weight/mL of the buffer for the binding assay.

[0254] For [³H]-glycine binding at the N-methyl-D-aspartate receptor, 20nanomolar [³H]-glycine (40-60 Ci/mmol, New England Nuclear, Boston,Mass.) is incubated with the membranes suspended in 50 millimolar tris(hydroxymethyl)aminomethane citrate, pH 7.1 for 30 minutes at 4° C.Glycine, 1 millimolar, is used to define the nonspecific binding. Bound[³H]-glycine is isolated from free using a Brandel (Biomedical Researchand Development Laboratories, Gaithersburg, Md.) cell harvester forvacuum filtration over glass fiber filters (Whatman GF/B from Brandel,Gaithersburg, Md.) presoaked in 0.025% polyethylenimine. The samplesretained on the glass fiber filters are rinsed 3 times with a total of2.5 mL ice cold buffer. Radioactivity is estimated by liquidscintillation counting. IC₅₀ values are obtained from a least-squaresregression of a logit-log transformation of the data. Typical IC₅₀values for compounds of the invention are usually less than 50 μM(micromolar) and are illustrated by the compound of Examples 1-6 (Ex. 1,2.4×10⁻⁷; Ex. 2, 1.2×10⁻⁷; Ex. 3, 3.7×10⁻⁷; Ex. 4, 2.4×10⁻⁷; Ex. 5,3.0×10⁻⁷; Ex. 6, 2.9×10⁻⁷ M).

[0255] Test B

[0256] Red Nucleus Test

[0257] The purpose of this test is to determine the effects ofintravenously administered glycine antagonists on the NMDA-inducedexcitatory response of red nucleus cells. HA-966 (racemic) and CGP 37849are reference agents that have been shown active in this test (ID50s of7.9 and 1.7 mg/kg iv, respectively).

[0258] The procedure for the red nucleus test is as follows. Rats areanesthetized with chloral hydrate (400 mg/kg ip) and the femoral vein iscatheterized for iv drug administration. Five-barrel micropipettes arestereotaxically positioned in the red nucleus. Typically, three to fourof the five barrels are filled as follows: the recording barrel with 2 Mpotassium citrate, the current balancing barrel with 4 M NaCl, the drugbarrel with 25 mM NMDA, and another drug barrel with 2.5 mM quisqualicacid (QA is only used in selectivity studies). NMDA is iontophoreticallyapplied with an ejection current that is adjusted depending on thesensitivity of each individual red nucleus cell. The NMDA is cycled onand off (usually 30-60 sec. on and 60-120 sec. off) and the firing rateof the cell during each period is recorded. Once the baseline firingrate of the cell has been established, the test drug is administered iv.The effect of the drug on the NMDA-induced excitatory response of thered nucleus cell can be both qualitatively and quantitatively evaluatedfrom the recordings and the raw data accumulated. Compounds of theinvention exhibited a antagonist response. For example, the compound ofexample 4 as the meglumine salt (N=3) had an ID50 of 3.770.

[0259] Test C

[0260] Rat Middle Cerebral Artery Test

[0261] Male SHR rats weighing 280-320 g are used for these studies. Themethod used for permanent middle cerebral artery (MCA) occlusion is asdescribed by Brint et al (1988). Briefly, focal ischemia is produced byoccluding first the left common carotid artery and then the left middlecerebral artery just superior to the rhinal fissure. Followingocclusions, drugs are administered intravenously via jugular catheter.Twenty-four hours after MCA/common carotid artery occlusion, the animalsare sacrificed and their brains quickly removed. Coronal sections of 1mm thickness are cut using a vibratome and stained with2,3,5-triphenyl-2H-tetrazolium chloride (TTC) dye. Following staining,necrotic tissue is readily distinguished from the intact brain and thearea of infarcted cortex can be traced on an image analyzer. The infarctvolume for each section is quantified with an image analyzer, and thetotal infarct volume is calculated with a program that summed allinterval volume. See S. Brint et al. J. Cerebral Blood Flow 8:474-485(1988). The statistical analysis of the difference between the volume ofischemic damage in the vehicle control and drug-treated animals isanalyzed by student's-t-test. All data are presented as the mean ±S. E.of the mean for n animals. compounds of the invention reduced ischemicdamage. For example, the compound of example 4 at an I.V. dose of 20mgs/kg/hr caused an infarct % volume change of −22%.

[0262] The invention will now be illustrated by the followingnon-limiting examples. In the Examples, unless stated otherwise:

[0263] (i) temperatures are given in degrees Celsius (° C.); operationswere carried out at room or ambient temperature, that is, at atemperature in the range of 18-25° C.;

[0264] (ii) evaporation of solvent was carried out using a rotaryevaporator under reduced pressure (600-4000 Pascals; 4.5-30 mm Hg) witha bath temperature of up to 60° C.;

[0265] (iii) flash chromatography was carried out on Merck Kieselgel(Art 9385) and column chromatography on Merck Kieselgel 60 (Art 7734);[these materials were obtained from E. Merck, Darmstadt, W. Germany];thin layer chromatography (TLC) was carried out on Analtech 0.25 mmsilica gel GHLF plates (Art 21521), obtainable from Analtech, Newark,Del., USA;

[0266] (iv) in general, the course of reactions was followed by TLC orHPLC and reaction times are given for illustration only;

[0267] (v) melting points are uncorrected and (d) indicatesdecomposition; the melting points given are those obtained for thematerials prepared as described; polymorphism may result in isolation ofmaterials with different melting points in some preparations;

[0268] (vi) all final products were essentially pure by TLC or HPLC andhad satisfactory nuclear magnetic resonance (NMR) spectra (300 MHz ¹HNMR in D-DMSO unless otherwise specified) and microanalytical data;

[0269] (vii) yields are given for illustration only;

[0270] (viii) chemical symbols have their usual meanings; the followingabbreviations have also been used: v (volume), w (weight); mp (meltingpoint), L [liter(s)], mL (milliliters), mM (millimoles), g [gram(s)], mg[milligram(s)], min (minutes), h (hour); and

[0271] (ix) solvent ratios are given in volume: volume (v/v) terms.

[0272] As the examples and in vitro or in vivo results indicate, thepresent invention or the compounds and glycine receptor antagonistsrecited herein are useful as in vitro tools for determining relativeglycine antagonist properties and as in vivo compounds or compositionswhich are useful as in vivo tools for determining relative antagonistproperties and as compounds or compositions which antagonize the glycinereceptor in animals or humans in need of treatment thereof. The presentinvention, therefore, also relates to a method of in vitro antagonism ofa mammalian glycine receptor comprising administering an antagonisteffective amount of a compound of formula I or Ia-Id wherein therespective variables (R¹- R⁸) are as recited previously. The inventionfurther relates to a method of in vivo antagonism of a mammalian,including human, glycine receptor comprising administering apharmacologically effective amount of a compound of formula I or Ia-Idto a mammal or a human wherein the variables for are as previouslydefined.

EXAMPLE 1 7-chloro-4-hydroxy-2-[1-(phenylcarbamoyl)ethyl]-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione

[0273] To a stirred suspension of2-pyrrolidinocarbamide-7-chloro-4-hydroxyquinoline-3-carboxylic acid(0.908 g, 2.8 mM) in tetrahydrofuran (36 mL) at ambient temperature wasadded dicyclohexylcarbodiimide(0.875 g, 4.2 mM). A tetrahydrofuransolution (18 mL) ofN-t-butoxycarbonyl-N′-[1-(phenyl-carbamoyl)ethyl]-hydrazine (1.18 g, 4.2mM, prepared by Method X described below) was immediately added to theabove suspension. The reaction mixture was stirred at room temperaturefor four hours. Upon completion of the coupling, the byproduct urea wasremoved via vacuum filtration. Partial purification by flash columnchromatography employing 5% methanol in chloroform provided thesemi-pure hydrazide in nearly quantitative yield. To the hydrazidesuspended in tetrahydrofuran (55 mL) was added methanesulfonic acid (6.0mL, 93 mM). The reaction was stirred at room temperature for 15 hours,concentrated in vacuo, and then poured into ice water (600 mL). Theresulting precipitate was isolated, dried, and triturated/sonicated withmethanol (20 mL) and isolated to yield after drying under vacuum at 50°C. 0.827 g (71%) of the title compound as an orange solid, mp>259° C.0.827 g (71%) of the title compound as an orange solid, mp> 250° C.; MS(CI): 411 (M+H).

[0274] Analysis for C₂₀H₁₅N₄O₄Cl:

[0275] Calculated: C, 58.47; H, 3.68; N, 13.64

[0276] Found: C, 58.20; H, 3.84; N, 13.43

[0277] 300 MHz ¹H NMR (DMSO-d₆): 1.52 (d, J=6.9, 3H), 5.54-5.64 (m, 1H),7.03 (t, J=7.4, 1H), 7.24-7.36 (m,2H), 7.41 (d, J= 8.0, 1H,), 7.66 (d,J=8.2, 2H,), 7.92 (s, 1H), 8.10 (d, J= 8.5, 1H), 10.08 (s, 1H), 11.88(s, 1H, ex), 12.65 (s, 1H, ex). The starting2-pyrrolidinocarbamide-7-chloro-4-hydroxy-quinoline-3-carboxylic acidwas prepared in the following manner:

[0278] To a suspension of3-carbomethoxy-2-pyrrolidino-carbamide-7-chloro-4-hydroxy quinoline(2.52 g, 7.5 mM) in de-ionized water (40 mL) was added dropwise asolution (20 mL) of an aqueous potassium hydroxide (882 mg, 15.75 mM).Upon complete addition, the reaction was warmed to 60° C. After 3 hours,the reaction was filtered to remove a small amount of insolublematerial. The filtrate was then acidified to pH=1 which yielded a whiteprecipitate. The solid was isolated by vacuum filtration, washed withwater, and dried at 30° C. under vacuum for 16 hours. This provided thedesired title compound (1.5 g, 64%) as a white solid, mp=225-8° C.; MS(cI): 321 (M+H).

[0279] 300 MHz ¹H NMR (DMSO-d₆): 8.12 (d, J=8.7 Hz, 1H), 7.60 (d, 1H,j=1.8 Hz), 7.47 (dd, 1H, J=8.8, 2.0 Hz), 3.69 (s, 3H), 3.40-3.49 (m,2H), 3.27-3.33 (m, 2H), 1.80-1.96 (m, 4H).

[0280] The starting3-carbomethoxy-2-pyrrolidinocarbamide-7-chloro-4-hydroxyquinoline wasprepared in the following manner:

[0281] To a suspension of3-carbomethoxy-7-chloro-4-hydroxyquinoline-2-carboxylic acid (2.25 g,8.0 mM) in tetrahydrofuran (20 mL) at ambient temperature under a N₂atmosphere was added dicyclohexylcarbodiimide (1.65 g, 8.0 mM) andpyrrolidine (0.596 g, 8.4 mM). The reaction was stirred room temperaturefor 15 hours after which time the byproduct urea was removed viafiltration. The desired product was purified via flash columnchromatography employing 5% methanol in chloroform to provide the titlecompound (2.52 g, 94.3%) as a tan solid, mp+215° C.; MS (CI): 335 (M+H).

[0282] 300 MHz ¹H NMR (DMSO-d₆): 8.12 (d, J=8.7 Hz, 1H), 7.60 (d, 1H,J=1.8 Hz), 7.47 (dd, 1H, J=8.8, 2.0 Hz), 3.69 (s, 3H), 3.40-3.49 (m,2H), 3.27-3.33 (m, 2H), 1.80-1.96 (m, 4H).

[0283] Hydrazine Preparation Method X

[0284] The startingN-t-butoxycarbonyl-N′-[1-(phenyl-carbamoyl)-ethyl]-hydrazine wasprepared in the following manner:

[0285] A mixture of t-butylcarbazate (2.87 g, 21.7 mM) and2-bromo-N-phenylpropionamide (1.07 g, 4.69 mM) in dimethyl formamide (6mL) was warmed to 50° C. To this mixture was added triethylamine (1.3mL, 9.33 mM). After stirring at 100° C. for 3 hours, the reactionmixture was poured into water (70 mL) and extracted with methylenechloride. The combined organic extracts were washed with water andbrine, dried over MgSO₄, and concentrated in vacuo. The crude productwas purified by flash column chromatography employing 3:1 diethylether:hexanes and 100% ether as eluants. This provided the titlecompound (1.18 g, 90%) as a white solid; MS (CI): 280 (M+H).

[0286] 300 MHz ¹H NMR (DMSO-d₆): 9.95 (br s, 1H), 8.50 (br s, 1H), 7.64(d, J=7.6, 2H), 7.27-7.37 (m, 2H), 7.00-7.10(m, 1H), 5.15 (br s, 1H),3.38-3.50 (m, 2H), 1.36 (s, 9H), 1.19 (d, J= 7.0, 3H).

[0287] N-t-BOC-N′-2-methyl benzyl hydrazine, N-t-BOC-N′-1-methylbutylhydrazine and N-t-BOC-N′-1,3-dimethylbutylhydrazine were alsoprepared according to this method.

[0288] Hydrazine Preparation Method Y

[0289] The starting N-t-butoxycarbonyl-N′-cyclohexylhydrazine wasprepared in the following manner:

[0290] To a solution of lithium aluminum hydride (2.2 g, 57.3 mM) intetrahydrofuran (100 mL) at room temperature under a N₂ atmosphere wasslowly added a tetrahydrofuran (25 mL) solution oft-butyl-2-cyclohexylidine carbazate (4.05 g, 19.1 nm). After 3 hours,the reaction was cooled to 0° C. and quenched by the slow addition ofsolid sodium sulfate decahydrate (75 g). This mixture was stirredvigorously for 1.5 hours prior to removing the undesired solid viavacuum filtration. The filtrate was concentrated and the productpurified by flash column chroma-tography employing 1:1 diethylether:hexane as eluant. This provided the title compound (2.55 g, 62%)as a white solid; MS (CI): 215 (M+H).

[0291] 300 MHz ¹H NMR (DMSO-d₆): 8.16 (br s, 1H), 4.12 (br s, 1H), 2.61(br s, 1H), 0.95-1.70 (m, 10H).

[0292] The starting t-butyl-2-cyclohexylidine carbazate was prepared inthe following manner:

[0293] Cyclohexanone (5.2 mL, 50.2 mM) and t-butyl carbazate (6..8 g,51.7 mM) were combined in hexane (70 mL) and heated to reflux for 30minutes under a N₂ atmosphere. The reaction was then cooled and theresulting precipitate was isolated via vacuum filtration and dried undervacuum to provide the title compound (9.57 g, 90%) as a yellowish-whitesolid; MS (EI): 212 (M+H).

[0294] 300 MHz ¹H NMR (DMSO-d₆): 9.51 (br s, 1H), 2.20-2.30 (m, 2H),2.10-2.20 (m, 2H), 1.35-1.65 (m, 15H).

[0295] Hydrazine Preparation Method Z

[0296] The startingN-t-butoxycarbonyl-N′-1-[1-methyl-2-15phenyl-ethyl]hydrazine wasprepared in the following manner:

[0297] To 1-phenyl-2-propanol (1.40 mL, 10 mM) in anhydrous methylenechloride (15 mL) cooled to −5° C. under a nitrogen atmosphere was addedtrifuoromethanesulfonic acid anhydride (2.08 mL, 11 mM) followed by2,6-lutidine (1.25 mL, 11 mM). The reaction was stirred at −5° C. forfive minutes then the reaction was warmed to 32° C. After two minutes, awarmed (32° C.) methylene chloride solution (20 mL) of t-butylcarbazate(5.2 g, 40 mM) was added to the reaction. The reaction was kept at 32°C. for 1.5 hours at which time the solvent was removed. The crudematerial was purified by flash column chromatography with 45-50% diethylether:hexanes as eluant yielding the title compound (0.901 g, 36%) as awhite solid after trituration with hexanes; MS (API+): 251, (M).

[0298] 300 MHz ¹H NMR (DMSO-d₆): 8.30 (br s, 1H), 7.15-7.29 (m, 5H),4.31 (br s, 1H), 3.00-3.20 (m, 1H), 2.74 (dd, J=4.9, 13.2, 1H), 2.36(dd, J=8.0, 13.2 1H), 1.39 (s, 9H), 0.82 (d, J= 6.3, 3H).

[0299] Following procedures similar to those described in Example 1, thefollowing compounds of the Formula I illustrated in Table 1 wereprepared. TABLE 1 The following Examples were made generally as setforth in Example I using appropriate corresponding precursors to makethe compounds listed. 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimidemetho-p-toluenesulfonate was employed in place ofdicyclohexylcarbodiimide in examples 2, 3, and 5-12 Analysis Ex. # NameYield m.p. MS(CI) NMR(DMSO-d₆) (cal'd/found) 17-chloro-4-hydroxy-2-[1-(N- 71 >250 411(M+H) 1.52 (d,J=6.9, 3H),5.54-5.64 (m, 1H), C₂₀H₁₅N₄O₄Cl: phenylcarbamoyl)ethyl]-1,2,5,10- 7.03(t,J=7.4, 1H), 7.24-7.36 (m, 2H), C = 58.47/58.20, tetrahydropyridazino[4,5-b]quinoline- 7.41 (d, J=8.0, 1H,), 7.66 (d,J=8.2, H =3.68/3.84, 1,10-dione. 2H,), 7.92 (s, 1H), 8.10 (d, J=8.5, 1H), N =13.64/13.43 10.08 (s, 1H), 11.88 (s, 1H, ex), 12.65 (s,1 H, ex) 27-chloro-4-hydroxy-2- 7% >300 345(M+H) 1.10-1.85 (m, 10H), 4.71-4.77C₁₇H₁₆N₃O₃Cl: cyclohexyl-1,2,5,10- (m, 1H), 7.40 (d,J=8.1 Hz, 1H),8.01(s, C = 59.05/58.71, tetrahydropyridazinol[4,5-b] 1H), 8.13 (d,J=8.6Hz, 1H), 11.84 (br s, H = 4.66/4.74, quinoline-1,10-dione 1H, exchange),12.39 (br s, 1H, exchange) N = 12.15/11.85 3 7-chloro-4-hydroxy-2-58 >250 382(M+H) 1.67 (d,J=8.2, 3H), 6.24 (dd, J=14.0, C₁₉H₁₄N₃O₃Cl:(1-methylbenzyl)-1,2,5,10- 7.0, 1H), 7.2-7.43 (m, 6H), 8.02 (d, J= C =62.05/62.33, tetrahydropyridazino[4,5-b] 1.9, 1H), 8.14 (d, J=8.6, 1H) H= 3.84/4.04, quinoline-1,10-dione N = 11.43/11.24 47-chloro-4-hydroxy-2- 48 237-239 334(M+H) 0.85 (t, J=7.0, 3H), 1.08-1.32(m, 5H), C₁₆H₁₆N₃O₃Cl: (1-methylbutyl)-1,2,5,10- 1.44-1.60 (m, 1H),1.68-1.86 (m, 1H), C = 57.58/57.52, tetrahydropyridazino[4,5-b]5.00-5.16 (m, 1H), 7.42 (d, J=8.6, 1H), H = 4.83/4.86,quinoline-1,10-dione 8.02 (s, 1H), 8.14 (d, J=8.6, 1H), 11.88 N =12.59/12.47 (s, 1H, ex), 12.44 (s, 1H, ex) 5 7-chloro-4-hydroxy-2- 52241-244 382(M+H) 1.27 (d, J=6.5, 3H), 2.82-2.91 (m, 1H),C₂₀H₁₆N₃O₃Cl.0.5 (1-methyl-2-phenylethyl)-1,2,5,10- 2.99-3.13 (m, 1H),5.22-5.33 (m, 1H), H₂O: tetrahydropyridazino[4,5-b] 7.10-7.42 (m, 6H),8.02 (s, 1H), 8.12 (d, C = 61.47/61.69, quinoline-1,10-dione J=8.7, 1H),11.71 (s, 1H), 12.29 (s, 1H) H = 4.38/4.50, N = 10.72/10.57 67-chloro-4-hydroxy-2- 49 238-240 348(M+H) 0.84 (t, J=6.2, 3H), 0.88 (d,J=5.9, 3H), C₁₇H₁₈N₃O₃Cl: (1,3-dimethylbutyl)-1,2,5,10- 1.20 (d, J=6.5,3H), 1.27-1.45 (m, 2H), C = 58.71/58.78 tetrahydropyridazino[4,5-b]1.71-1.83 (m, 1H), 5.10-5.23 (m, 1H), H = 5.22/5.21,quinoline-1,10-dione 7.42 (dd, J=8.6, 1.7, 1H), 8.02 (s, 1H), N =12.08/12.03 8.14 (d,J=8.6, 1H), 11.88 (s, 1H, ex), 12.44 (s, 1H, ex) 77-chloro-4-hydroxy-2-[(R)- 39 262-4  350(M+H) 1.51 (d, J=7.2, 3H), 3.65(s, 3H), 5.4- C₁₅H₁₂N₃O₅Cl.0.7 1-(methyloxycarbonyl)ethyl]-1,2,5, 5.5(dd, J=7.0, 14.1, 1H), 7.30 (d, J= H₂O: 10-tetrahydropyridazino[4,5-b]8.6, 1H), 8.03 (s, 1H), 8.15 (d, J=8.6, C = 49.72/49.77,quinoline-1,10-dione 1H), 12.00 (s, 1H, ex), 12.75 (s, 1H, ex) H =3.73/3.60, N = 11.60/11.61 8 7-chloro-4-hydroxy-2-[1- 62 242-4  412(M+H)3.71 (s, 3H), 6.60 (s, 1H), 7.30-7.49 (m, C₂₀H₁₄N₃O₅Cl.0.8(methyloxycarbonyl)benzyl]- 6H), 8.04 (d, J,=1.4, 1H), 8.15, d, J,= H₂O:1,2,5,10-tetrahydropyridazino 8.67, 1H), 12.01 (br s, 1H, ex), 12.71 (brs, C = 56.36/56.27, [4,5-b]quinoline-1,10-dione 1H, ex) H = 3.69/3.80, N= 9.86/9.73 9 7-chloro-4-hydroxy-2-[1-(N-phenyl-N-  3 170-80  425(M+H)1.29-1.40 (m, 3H), 3.16 (s, 3H), 5.23-5.46 C₂₁H₁₇N₄O₄Cl.1.25 methylcarbamoyl)ethyl]-1,2,5,10- (m, 1H), 7.15-7.50 (m, 6H), 8.0 2(s, 1H),H₂O: tetrahydropyridazino[4,5-b]quinoline- 8.11 (d,J=8.6, 1H), 11.87 (brs, 1H, ex), C = 56.38/56.06, 1,10-dione. 12.58 (br s, 1H, ex) H =4.39/3.99, N = 12.52/12.83 10  7-chloro-4-hydroxy-2-[1-methyl-2-(N-61 >250 425(M+H) 1.31 (d,J=6.6, 3H), 2.65-2.86(m, 2H) C₂₁H₁₇N₄O₄Cl:phenyl carbamoyl)ethyl]-1,2,5,10- 5.37-5.54 (m, 2H), 7.01 (t, J=7.3,1H), C = 59.37/59.05, tetrahydro pyridazino[4,5-b]quinoline- 7.22-7.32(m, 2H), 7.42 (d, J=8.5, 1H), H = 4.03/4.11, 1,10-dione. 7.55 (d, J=7.7,2H), 8.01 (s, 1H), 8.14 (d, N = 13.19/13.03 J=8.6, 1H), 9.99 (s, 1H),11.88 (br s, 1H), 12.45 (br s,1H) 11 7-chloro-4-hydroxy-2-[1-methyl-2-(N- 13 218-9  439(M+H) 1.16 (d,J=4.9,3H), 2.43 (br s, 2H), 3.13 C₂₂H₁₉N₄O₄Cl:phenyl-N-methylcarbamoyl)ethyl]- (s, 3H) 5.42 (q, J=6.5, 1H), 7.28-7.55(m, C = 60.21/59.85, 1,2,5,10-tetrahydropyridazino[4,5- 6H), 8.01 (s,1H), 8.14 (d, J=8.5, 1H), H = 4.36/4.29, b]quinoline-1,10-dione. 11.85(br s, 1H), 12.38 (br s, 1H) N = 12.77/12.58 12 7-chloro-4-hydroxy-2-(1-  5 237-8  422(M+H) 1.91 (q,J=8.7, 1H),7.42-7.50 (m, 4H), C₁₉H₁₁N₃O₃F₃Cl.0.28 trifluoromethylbenzyl)-1,2,7.62-7.72 (m, 2H), 8.05 (s, 1H), 8.14 (d, J= H₂O · 0.15 CH₃OH:5,10-tetrahydropyridazino 8.7, 1H), 12.08 (s, 1H), 12.90 (s, 1H) C =53.29/53.31, [4,5-b]quinoline-1,10-dione H = 2.84/2.93, N = 9.74/9.65

EXAMPLE 137-chloro-4-hydroxy-2-[(R)-1-carboxyethyl]-1,2,5-10-tetrahydro-pyridazino[4,5-b]quinoline-1,10-dione

[0300] To7-chloro-4-hydroxy-2-[(R)-1-(methyloxycarbonyl)ethyl]-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione(500 mg, 1.43 mM) in 20 ml of water with added potassium hydroxide (240mg, 4.28 mM). The remnants were washed into the reaction vessel withabout 2 ml of water. The reaction mixture formed a white slurry. Thismixture was then refluxed for 30 minutes, causing the reaction to becomeclear, at which point 98% of the ester had been converted to the acid asanalyzed by HPLC. The reaction was then cooled to 0° C. in an ice bath.Hydrochloric acid (1N, approximately 15 ml) was then added dropwiseuntil the pH<7. A white solid gradually fell out of solution over a 30minute period. This solid was isolated, dried and triturated/sonicatedwith methanol (10 ml) and filtered to yield after drying under vacuum at40° C. 455 mg (95%) of the title compound as a white solid, mp>275° C.MS (Cl): 236 (M+H).

[0301] Analysis for C₁₄H₁₀N₃O₅Cl 1.0 H₂O

[0302] Calculated: C, 47.54; H, 3.42: N, 11.88

[0303] Found: C, 47.89; H, 3.73; N, 11.42

[0304]300 MHz ¹H NMR (DMSO-d₆): 1.51 (d, J=7.1, 3H), 5.42 (dd, J=7.1,14.8, 1H) 7.43 (dd, J=2.0, 14.8, 1H), 8.03 (d, J=2.0, 1H), 8.15 (d,J=8.7, 1H), 12.67 (br s, 1H).

[0305] Following a procedure similar to that described in Example 13,the following compounds of the Formula I illustrated in Table 2 wereprepared. TABLE 2 Ex. MS NMR Analysis # Name Yield m.p. (CI) (DMSO -d₆)(cal'd/found) 14 7-chloro-4- 71 >250 411 1.52 (d, j = C₂₀H₁₅N₄O₄Cl:hydroxy-2- (M + 6.9, 3H), C=58.47/58.20, (1-carboxy- H) 5.54-5.64H=3.68/3.84, benzyl)-1, (m, 1H), N=13.64/13.43 2,5,10-tet- 7.03 (t, j =rahydro 7.4, 1H), pyridazino 7.24-7.36 [4,5-b] (m, 2H) quinoline-1, 7.41(d, j = 10-dione. 8.0, 1H,) 7.66 (d, j = 8.2, 2H,) 7.92 (s, 1H) 8.10 (d,j = 8.2, 2H,) 7.92 (s, 1H), 8.10 (d, j = 8.5, 1H), 10.08 (s, 1H) 11.88(s, 1H, ex), 12.65 (s,1H, ex)

[0306] The appropriate R²-substituted hydrazines which are required forthe synthesis of the compounds of the Formula I can be prepared as shownin Tables 3 and 4. TABLE 3 The following BOC-protected hydrazines weremade generally as set forth in Method X, using appropiate correspondingprecursor to make the compounds listed. Prepar- ation # Name YieldMS(CI) NMR (DMSO -d₆) 1 N-t-butoxycarbonyl- 90 280 1.19 (d, j = 7.0,3H), N′-[1-9N- (M + H) 1.36 (s, 9H), 3.38- phenylcarbamoyl) 3.50 (m,2H), 5.15 (br ethyl]hydrazine s, 1H), 7.00-7.10(m, 1H), 7.27-7.37 (m,2H), 7.64 (d, J = 7.6, 2H), 8.50 (br s, 1H), 9.95 (br s, 1H). 2N-t-butoxy- 80 237 1.16 (d, j = 6.5, 3H), carbonyl-N′-1- (M + H) 1.35(s, 9H), 4.07 (br methylbutyl- s, 1H), 4.53-4.59 hydrazine (m, 1H),7.05-7.35 (m, 5H), 8.16 (br s, 1H). 3 N-t-butoxy- 68 203 0.83-0.93 (m,6H), carbonyl-N′-1- (M + H) 1.00-1.43 (br m, methylbutyl- 4H), 1.38 (brs, 9H), hydrazine 2.73-2.87 (br s, 1H), 4.11 (br s, 1H), 8.18 (br s,1H). 4 N-t-butoxy- 22 217 0.82 (d, j = 6.6, 3H), carbonyl-N′-1,3- (M +H) 0.87 (d, j = 6.6, 6H), dimethyl- 0.92-1.06 (m , 2H), butylhydrazine1.17-1.29 (m, 1H), 1.38 (br s, 9H), 1.57- 1.74 (m, 1H), 7.42 (dd, j =8.6, 1.7, 1H) 8.02 (s, 1H), 2.79- 2.97 (m, 1H), 4.11 (br s, 1H), 8.20(br s, 1H) 5 N-t-butoxycarbonyl- 83 294 0.93 (d, j = 6.2, 3H), N′-[1-(N-(M + H) 1.36 (s, 9H), 3.15 phenyl-N- (s, 3H), 3.34-346 methylcarbamoyl)-(br s, 1H), 4.32- hydrazine 4.43 (br s, 1H), 7.28 (d, j = 7.6, 2H)732-7.50 (m, 3H), 7.93-8.14 (br s, 1H).

[0307] TABLE 3 The following BOC-protected hydrazines were madegenerally as set forth in Method Z, using appropriate correspondingprecursor to make the compounds listed. Prepar- ation # Name YieldMS(CI) NMR (DMSO -d₆)  6 N-t-butoxycarbonyl- 94 219 1.11 (d, j = 7.0,3H), N′-[(R)-1- (M + H) 1.36 (s, 9H), 3.50- (methyloxy- 3.60 (m, 1H),3.60 (s, carbonyl)-ethyl] 3H), 4.70 (br s, 1H, hydrazine ex) 8.21 (br s,1H,  7 N-t-butoxycarbonyl- 83 225 ex). N′-[1- (M − tBu) (methyloxy-carbonyl)-benzyl]- hydrazine  8 N-t-butoxycarbonyl- 293 N′-[1-methyl-(M + H) 2-(N-phenyl carbamoyl) ethyl]-hydrazine  9 N-t-butoxycarbonyl-57 308 0.82 (d, j = 5.8, 3H), N′-[1-methyl- (M + H) 1.36 (s, 9H), 1.77-2-(N-phenyl-N- 1.93 (m, 1H), 2.07- methylcarbamoyl) 2.23 (m, 1H), 3.14(s, ethyl]-hydrazine 3H), 4.32 (br s, 1H), 7.27-7.52 (M, 5H), 8.07 (brs, 1H) 10 N-t-butoxycarbonyl- 73 1.35 (s, 9H), 4.59- N′-1-trifluoro-4.75 (m, 1H), 5.34 (s, methylbenzyl- 1H), 7.36-7.50 (m, hydrazine 5H),8.49 (s, 1H).

[0308] The following illustrate representative pharmaceutical dosageforms containing a compound of formula I or Ia-Id, or a pharmaceuticallyacceptable salt thereof, for example as illustrated in Examples 1-14(hereinafter referred to as “compound X”), for therapeutic orprophylactic use in humans:

EXAMPLE 15

[0309] (a) Tablet mg/tablet Compound X 50.0 Mannitol, USP 223.75Croscarmellose sodium 6.0 Maize starch 15.0 Hydroxypropylmethylcellulose(HPMC), USP 2.25 Magnesium stearate 3.0

[0310] (b) Capsule Compound X 10.0 Mannitol, USP 488.5 Croscarmellosesodium 15.0 Magnesium stearate 1.5

[0311] The above formulations may be obtained by conventional procedureswell known in the pharmaceutical art. The tablets may be enteric coatedby conventional means, for example to provide a coating of celluloseacetate phthalate.

EXAMPLE 16

[0312] This is an example of a formulation suitable for parenteral usemade with the compound of Example 4: Parenteral Formulation: mg/mLCompound 10.0 Meglumine 19.5 Dextrose, anhydrous 39.5 Sterile Water forInjection qs ad 1 mL

[0313] The solution was prepared by conventional measures well known inthe pharmaceutical field. General formulations for this class ofcompounds and their salts, other than for acylated compounds, may beprepared by solubilizing the active compound in an aqueous meglumine(N-methyl-glucamine) solution containing an equimolar, or ifsolubilization is difficult, a molar excess of meglumine relative toCompound. Choline salts are preferred for use in making formulations.Excipients such has dextrose may be added to adjust the osmolality ofthe formulation. Water for Injection is added to bring the solution tofinal volume. Alternately, other amine bases such as tromethamine or1-arginine may be used to solubilize the active compound.

EXAMPLE 17

[0314] A formulation is made as in Example 16, except that the cholinesalt of Compound X is used in place of the compound of Example 4.

EXAMPLE 18

[0315] A formulation is made comprising a 5% aqueous solution ofdextrose made to 10 mg/mL in the choline salt of Compound X.

[0316] The previous examples are considered to be non-limiting and thus,the compounds of formula I or Ia-Id and pharmaceutical compositionscontaining same may be used to treat and/or prevent stroke and the otherdiseases as related herein. Schemes 1 and 2 presented hereinbefore andthe following formulae are presented to clarify how to make thecompounds of the invention. Table 1 shows compounds of the invention.The formula pages describe formula I, groups R2′-R2″′, and formulaIa-Id. Scheme 1 describes how compounds of the invention were or may beprepared. Scheme 2 describes how the starting BOC-protected hydrazinesmay be prepared.

What is claimed is:
 1. A compound of the Formula I:

or a pharmaceutically acceptable salt thereof and/or a tautomer thereof,and/or a hydrate thereof, and/or a solvate thereof; and/or astereoisomer thereof; wherein: Ring A is chosen from an ortho fusedaromatic or heteroaromatic five- or six-membered ring selected fromphenyl, pyridyl, furyl, pyrrolyl or thienyl either unsubstituted ormulti-substituted at a ring carbon atom with R¹ wherein R¹ isindependently selected from the group consisting of halo, (1-4C)alkyl,NO₂, CN, (C1-3)perfluoroalkyl, OH, OCF₃, (2-4C)alkenyl, (2-4C)alkynyl,O(1-4C)alkyl, NR′R″, SO₂NR′R″, SO_(m)R′, a heterocyclic group, NR′COR″,COR″, NR′CO₂R″, CO₂R′, or CONR′R″; R² is selected from a cycloalkylmoiety of 3-7 carbon atoms; or R² is selected from a group of theformula R2′, R2″ or R2″′ wherein R2′ is —CHR (CH₂)_(n)C(O)NR⁵R⁶; R2″ is—CHR³ (CH₂)R⁴ and R2″′ is —CHR³(CH₂)_(n)L wherein, for a group offormula R2″′, L is M or M is phenyl or benz derivatives thereof and iseither unsubstituted or substituted with 1, 2, 3 or 4 groups chosen from—O-(1-4C)alkyl, —O-(2-4C)alkenyl, —O—(2-4C)alkynyl,—O(C0-C6alkyl)phenyl, —OH, -halo, —NO₂, —CN, —CF₃, -(1-4C)alkylCF₃,—NH(CO)R′, -(1-4C)alkyl, —NR′R″, —CO₂R′, —CONR′R″, —SO_(m)R′, —SO₂NR′R″,(C1-C6)alkyloxy(C1-C6)alkyloxy-, hydroxy(C1-C6)alkyloxy-,oxy(1-6C)alkyloxy which may form a cyclic ring attached to the phenylring in an ortho manner, aryloxy(1-4C)alkyloxy(1-4C)alkyl,(C1-C6)alkyloxy(C1-C6)alkyloxy(C1-C6)alkyloxy-,hydroxy(C1-C6)alkyloxy(C1-C6)alkyloxy-, —O(C1-C6alkyl)NR′R″,—NR′(C1-C6alkyl)NR′R″, -(C1-C6alkyl)NR′R″, —0—(1-4C)perfluroalkyl,-(1-4C)perfluroalkyl, —NR′(C1-C6alkyloxy), —NR′(C1-C6alkylhydroxy),-(C1-4alkyl)oxy(C1-4alkyl), —O(C1-4alkyl)COOR′, —(CH)_(n)NR′R″COOR′wherein n is 1-4, -(C1-4alkyl)NR′R″, -(C1-4alkyl)OR′,—NR′(CH₂)_(n)COOR′, —S(O)_(m)(C1-4alkyl)oxy(C1-4alkyl) ,—S(O)_(m)(C1-4alkyl)oxy(C1-4alkyl)oxy(C1-4alkyl),—NR′(C1-4alkyl)oxy(C1-4alkyl),—NR′(C1-4alkyl)oxy(C1-4alkyl)oxy(C1-4alkyl); heterocycle whereinheterocycle is selected from a five- and/or six- and/or seven-memberedheterocyclic ring containing 1, 2, or 3 heteroatoms chosen from O, N, orS, or aryl or heteroaryl benz derivatives thereof, wherein the N on theheterocycle is optionally substituted with R′ and a carbon or nitrogenatom on the heterocycle may be substituted with R or R′ or a carbon atommay be disubstituted to form a C5-C7 spiral group or a carbon atom orsulfur atom may be substituted with O to form a carbonyl group orsulfonyl group (S(O)_(m)) with the proviso that a heterocyclic nitrogenmay not be attached to a nitrogen on the tricyclic ring system offormula I; heteroaryl wherein heteroaryl is selected from unsubstitutedor substituted aromatic species and benz derivatives thereof includingpyridyl, thienyl, furanyl, or those groups containing two heteroatomsselected from N, O or S such as pyrazole, imidazole, isoxazole, oxazole,thiazole or isothiazole (and oxidized versions thereof selected fromS(O)_(m) wherein m is 0-2), pyridazine, pyrimidine, pyrazine or thosegroups containing three heteroatoms chosen from N, O or S such astriazole or oxadiazole or triazine, or those groups containing fourheteroatoms such as tetrazole, wherein the N on the heteroaryl group isoptionally substituted with R and the substituted aromatic substituentsare selected from hydroxy, alkoxy, halo or cyano and the heteroarylgroup is attached to —(CH₂)_(n) via a carbon atom or a heteroatom on theheteroaryl group; W is selected from OH, OR′, OCOR′, S(O)_(m)R′,S(O)_(m)NR′R″, halo, CF₃₁ NR′R″ or W is COR′, NR′COR″, OCONR′, NRCO₂R′,(C3-6)cycloalkyl, NRCONR′R″, CO₂R′, or CONRR′; n is chosen from 0-6; Zis selected from oxo, —OH, H, H—, H,(1-6C)alkyl or (1-6C)alkylarylwherein aryl may be substituted with a substituent or substituentsselected from halogen or C1-6alkyl; R³ is selected from (1-6C)alkyl,(0-6C)alkylCF₃, (0-6C)alkylCOOR; R⁷ is selected from hydrogen or —(CO)R⁸wherein R⁸ is selected from (1) hydrogen, (2) (1-12C)alkyl which maycontain a double or triple bond, and which may bear a group selectedfrom (a) CN, OR^(e), and CO₂R^(e), wherein R^(e) is selected fromhydrogen, (1-4C)alkyl, and phenyl and phenyl(1-4C)alkyl, the phenylrings of which can be substituted with from 0-3 substituents selectedfrom halo, amino, hydroxy, cyano, nitro, (1-4C)alkyl, and (1-4C)alkoxy;(b) NR^(f) ₂ and CONR^(f) ₂ wherein each R^(f) is independently selected(1) from R^(h), COR^(h), and COOR^(h) when the said group is NR^(f) ₂and (2) from the values of R^(h) when the said group is CONR^(f) ₂wherein R^(h) can have any of the values stated above for R^(e), orwherein, for either of the said groups, the two R^(f) values, togetherwith the nitrogen to which they are attached, form a saturated 4- to7-membered ring, (3) NR^(g) ₂ wherein each R^(g) can independently haveany of the values stated above for R^(e), or wherein the two R^(g)groups together with the nitrogen to which are attached form a saturated4- to 7-membered ring, (4) pyridyl, pyridyl(1-12C)alkyl, (5) phenyl, andphenyl(1-4C)alkyl wherein the phenyl rings can be substituted with from0-3 substituents selected from halo, amino, hydroxy, cyano, nitro,(1-4C)alkyl, and (1-4C)alkoxy; R is selected from H or (1-4C)alkyl; R′and R″ are independently selected from H, (1-4C)alkyl wherein alkylincludes alkenyl(C2-C4) and alkynyl(C2-C4); (3-6C)cycloalkyl,Phenyl(0-4C)alkyl-, heterocycle(0-4C)alkyl- or heteroaryl(0-4C)alkyl-wherein phenyl or heterocycle or heteroaryl is as defined above and anyof the above is optionally substituted at one or more carbon atoms withhalo, H, (1-4C)alkyl, (3-6C)cycloalkyl, phenyl, NO₂, CN, CF₃, OH,O-(1-4C)alkyl, NR′R″S(O)₂R′ or SO₂NR′R″ wherein NR′R″ may optionallyform an N-alkyl(C1-3)oxyalkyl(C2-3) ring with N; for a group of formulaR2′, R⁵ is selected from aryl wherein the aryl group may beunsubstituted or mono- or multisubstituted with a substituent selectedfrom halogen, (1-4C)alkyl, NO₂, CN, (C1-3)perfluoroalkyl, OH, OCF₃,(2-4C)alkenyl, (2-4C)alkynyl, O(1-4C)alkyl, NR′R″, SO₂NR′R″, SO_(m)R′,NR′COR″, COR″, NR′CO₂R″, CO₂R′, or CONR′R″; and R⁶ is chosen from(1-6C)alkyl or hydrogen; for a group of formula R2″, R⁴ is selected from(1-6C)alkyl, (2-6C) alkyl containing a double or triple bond, or(0-6C)alkylaryl wherein the aryl moiety may be unsubstituted orsubstituted or multisubstituted with a substituent selected fromhalogen, (1-4C)alkyl, NO₂, CN, (C1-3)perfluoroalkyl, OH, OCF₃,(2-4C)alkenyl, (2-4C)alkynyl, O(1-4C)alkyl, NR′R″, SO₂NR′R″, SO_(m)R′,NR′COR″, COR″, NR′CO₂R″, CO₂R′, or CONR′R″; and m is chosen from 0-2. 2.A compound of the Formula Ia:

according to claim 1 .
 3. A compound according to claim 2 wherein: theRing A phenyl ring is mono, di or trisubstituted with R¹ wherein R¹ isselected from halo, (1-4C)alkyl or nitro; R² is selected from acycloalkyl moiety of 5-7 carbon atoms, or R² is selected from a group ofthe Formulas R2′, R2″ or R2″′ wherein n is chosen from 0-2; R⁵ is phenylwherein the phenyl group is unsubstituted or mono- or multisubstitutedwith a substituent selected from halogen, (1-4C)alkyl, NO₂, CN,(C1-3)perfluoroalkyl, OH, OCF₃, (2-4C)alkenyl, (2-4C)alkynyl, or0(1-4C)alkyl; R⁶ is chosen from (1-3C)alkyl or hydrogen; R⁴ is selectedfrom (1-3C)alkyl or (0-3C)alkylphenyl wherein the phenyl moiety isunsubstituted or substituted with a substituent selected from halogen,(1-4C)alkyl, NO₂, CN, (C1-3)perfluoro-alkyl, OH, OCF₃, (2-4C)alkenyl,(2-4C)alkynyl, or O(1-4C)alkyl; L is phenyl, or CO₂R′ wherein R′ ishydrogen or (1-4C)alkyl; and R⁷ is selected from hydrogen or (1-3C)alkylC(O)—.
 4. A compound according to claim 3 wherein: the ring A phenylring is mono-substituted with R¹ wherein R¹ is halo; R² is cyclohexyl,or R² is selected from a group of the Formulas R2′, R2″ or R2″′ whereinn is 0-2; R⁵ is phenyl wherein the phenyl group is unsubstituted; R⁴ is(1-3C)alkyl or (0-3C)alkylphenyl wherein the phenyl moiety isunsubstituted; L is phenyl or CO₂R′ wherein R′ is hydrogen or(1-4C)alkyl; and R⁷ is hydrogen.
 5. A compound according to claim 4wherein: the Ring A phenyl ring is mono-substituted with R¹ wherein R¹is chloro; R²is cyclohexyl, or R² is selected from a group of theformula R2′, R2″ or R2″′ wherein n is 0-2; R⁵ is phenyl; R⁶ is hydrogenor methyl; R⁴ is methyl, isopropyl, or phenyl; L is phenyl or CO₂R′wherein R′ is hydrogen or methyl; R⁷ is hydrogen; and R³ is methyl,trifluoromethyl, CO₂H or CO₂CH₃.
 6. A compound according to claim 5selected from the group consisting of:7-chloro-4-hydroxy-2-[1-(N-phenylcarbamoyl)ethyl]-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione,7-chloro-4-hydroxy-2-cyclohexyl-1,2,5,10-tetrahydro-pyridazino[4,5-b]quinoline-1,10-dione,7-chloro-4-hydroxy-2-(1-methylbenzyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione,7-chloro-4-hydroxy-2-(-1-methylbutyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione,7-chloro-4-hydroxy-2-(1-methyl-2-phenylethyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione,7-chloro-4-hydroxy-2-(-1,3-dimethylbutyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione,7-chloro-4-hydroxy-2-[(R)-1-(methyloxycarbonyl)ethyl]-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione,7-chloro-4-hydroxy-2-[l-(methyloxycarbonyl)benzyl]-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione,7-chloro-4-hydroxy-2-[1-(N-phenyl-N-methylcarbamoyl)ethyl]-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione,7-chloro-4-hydroxy-2-[1-methyl-2-(N-phenylcarbamoyl)ethyl]-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione,7-chloro-4-hydroxy-2-[1-methyl-2-(N-phenyl-N-methyl-carbamoyl)ethyl]1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione,7-chloro-4-hydroxy-2-(1-trifluoromethylbenzyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione,7-chloro-4-hydroxy-2-(1-carboxybenzyl)-1,2,5,10-tetra-hydropyridazino[4,5-b]quinoline-1,10-dione, and7-chloro-4-hydroxy-2-[(R)-1-carboxyethyl]-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione.
 7. A compound according to claim 1 whereinR³ is selected from (1-6C)alkyl, (0-6C)alkyl or (0-6C)alkylCOOH.
 8. Acompound according to claim 7 selected from the group consisting of:7-chloro-4-hydroxy-2-[1-(N-phenylcarbamoyl)ethyl]-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione,7-chloro-4-hydroxy-2-cyclohexyl-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione,7-chloro-4-hydroxy-2-(1-methylbenzyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione,7-chloro-4-hydroxy-2-(1-methylbutyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione,7-chloro-4-hydroxy-2-(1-methyl-2-phenylethyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione, and7-chloro-4-hydroxy-2-(1,3-dimethylbutyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione.
 9. A compound according to claim 1 whereinR² is cyclohexyl.
 10. A compound according to claim 1 wherein R² is agroup of the formula R2′.
 11. A compound according to claim 1 whereinR²is a group of the formula R2″.
 12. A compound according to claim 1wherein R² is a group of the Formula R2″′.
 13. A pharmaceuticalcomposition comprising a compound according to anyone of claims 1-12 anda pharmaceutically acceptable excipient or diluent.
 14. A method for thetreatment of neurological disorders comprising administering to apatient in need of such treatment an effective amount of a compoundaccording to anyone of claims 1-12.
 15. A process for producing acompound according to claim 1 which comprises: (a) reacting a compoundof the Formula IV:

with a hydrazine of the formula:

to produce a compound of the Formula II

and (b) reacting said compound of the Formula II with an acid to affordthe compounds of the Formula I.